The rates of G:C[yields]T:A and G:C[yields]C:G transversions at CpG dinucleotides in the human factor IX gene

Energy Technology Data Exchange (ETDEWEB)

Ketterling, R.P.; Vielhaber, E.; Sommer, S.S. (Mayo Clinic/Foundation, Rochester, MN (United States))

1994-05-01

The authors have identified eight independent transversions at CpG in 290 consecutive families with hemophilia B. These eight transversions account for 16.3% of all independent transversions in the sample, yet the expected frequency of CpG transversions at random in the factor IX gene is only 2.6% (P<0.1). The aggregate data suggest that the two types of CpG transversions (G:C[yields]T:A and G:C[yields]C:G) possess similar mutation rates (24.8 [times] 10[sup [minus]10] and 20.6 [times] 10[sup [minus]10], respectively), which are about fivefold greater than the comparable rates for transversions at non-CpG dinucleotides. The enhancement of transversions at CpG suggest that the model by which mutations occur at CpG may need to be reevaluated. The relationship, if any, between deamination of 5-methyl cytosine and enhancement of transversions at CpG remains to be defined. 28 refs., 2 tabs.

CpG + CpNpG Analysis of Protein-Coding Sequences from Tomato

DEFF Research Database (Denmark)

Hobolth, Asger; Nielsen, Rasmus; Wang, Ying

2006-01-01

We develop codon-based models for simultaneously inferring the mutational effects of CpG and CpNpG methylation in coding regions. In a data set of 369 tomato genes, we show that there is very little effect of CpNpG methylation but a strong effect of CpG methylation affecting almost all genes. We...... further show that the CpNpG and CpG effects are largely uncorrelated. Our results suggest different roles of CpG and CpNpG methylation, with CpNpG methylation possibly playing a specialized role in defense against transposons and RNA viruses....

Verification of Carbon Sink Assessment. Can We Exclude Natural Sinks?

International Nuclear Information System (INIS)

Alexandrov, G.; Yamagata, Y

2004-01-01

Any human-induced terrestrial sink is susceptible to the effects of elevated atmospheric CO2 concentration, nitrogen deposition, climate variability and other natural or indirect human-induced factors. It has been suggested in climate negotiations that the effects of these factors should be excluded from estimates of carbon sequestration used to meet the emission reduction commitments under the Kyoto Protocol. This paper focuses on the methodologies for factoring out the effects of atmospheric and climate variability/change. We estimate the relative magnitude of the non-human induced effects by using two biosphere models and discuss possibilities for narrowing estimate uncertainty

The impact of intragenic CpG content on gene expression.

Science.gov (United States)

Bauer, Asli Petra; Leikam, Doris; Krinner, Simone; Notka, Frank; Ludwig, Christine; Längst, Gernot; Wagner, Ralf

2010-07-01

The development of vaccine components or recombinant therapeutics critically depends on sustained expression of the corresponding transgene. This study aimed to determine the contribution of intragenic CpG content to expression efficiency in transiently and stably transfected mammalian cells. Based upon a humanized version of green fluorescent protein (GFP) containing 60 CpGs within its coding sequence, a CpG-depleted variant of the GFP reporter was established by carefully modulating the codon usage. Interestingly, GFP reporter activity and detectable protein amounts in stably transfected CHO and 293 cells were significantly decreased upon CpG depletion and independent from promoter usage (CMV, EF1 alpha). The reduction in protein expression associated with CpG depletion was likewise observed for other unrelated reporter genes and was clearly reflected by a decline in mRNA copy numbers rather than translational efficiency. Moreover, decreased mRNA levels were neither due to nuclear export restrictions nor alternative splicing or mRNA instability. Rather, the intragenic CpG content influenced de novo transcriptional activity thus implying a common transcription-based mechanism of gene regulation via CpGs. Increased high CpG transcription correlated with changed nucleosomal positions in vitro albeit histone density at the two genes did not change in vivo as monitored by ChIP.

The CpG island methylator phenotype: What's in a name?

NARCIS (Netherlands)

L.A.E. Hughes (Laura A.); V. Melotte (Veerle); J.D. Schrijver (Joachim De); M.P.M. de Maat (Moniek); V.T.H.B.M. Smit (Vincent); J.V.M.G. Bovée (Judith); P.J. French (Pim); P.A. van den Brandt (Piet); L. Schouten (Leo); T. Meyer (Thorsten); W. van Criekinge (Wim); N. Ahuja (Nita); J.G. Herman (James); M.P. Weijenberg (Matty); M. van Engeland (Manon)

2013-01-01

textabstractAlthough the CpG island methylator phenotype (CIMP) was first identified and has been most extensively studied in colorectal cancer, the term "CIMP" has been repeatedly used over the past decade to describe CpG island promoter methylation in other tumor types, including bladder, breast,

Identification of a boron nitride nanosphere-binding peptide for the intracellular delivery of CpG oligodeoxynucleotides

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Zhang, Huijie; Yamazaki, Tomohiko; Zhi, Chunyi; Hanagata, Nobutaka

2012-09-01

CpG oligonucleotides (CpG ODNs) interact with Toll-like receptor 9 (TLR9), which results in the induction of immunostimulatory cytokines. We delivered CpG ODNs intracellularly using boron nitride nanospheres (BNNS). To enhance the loading capacity of CpG ODNs on BNNS, we used a phage display technique to identify a 12-amino acid peptide designated as BP7, with specific affinity for BNNS, and used it as a linker to load CpG ODNs on BNNS. The tyrosine residue (Y) at the eighth position from the N-terminus played a crucial role in the affinity of BP7 to BNNS. BNNS that bound BP7 (BNNS-BP7) were taken up by cells and showed no cytotoxicity, and CpG ODNs were successfully crosslinked with BP7 to create BP7-CpG ODN conjugates. Using BP7 as a linker, the loading efficiency of CpG ODNs on BNNS increased 5-fold compared to the direct binding of CpG ODNs to BNNS. Furthermore, the BP7-CpG ODN conjugate-loaded BNNS had a greater capacity to induce interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) production from peripheral blood mononuclear cells (PBMCs) than that of CpG ODNs directly loaded on BNNS. The higher amount of cytokine induction by BP7-CpG ODN conjugate-loaded BNNS may be attributed to a higher loading capacity and stronger binding to BNNS of the linker BP7. The greater functionality of BP7-conjugated CpG ODNs on BNNS expands the potential of BNNS for drug delivery applications.CpG oligonucleotides (CpG ODNs) interact with Toll-like receptor 9 (TLR9), which results in the induction of immunostimulatory cytokines. We delivered CpG ODNs intracellularly using boron nitride nanospheres (BNNS). To enhance the loading capacity of CpG ODNs on BNNS, we used a phage display technique to identify a 12-amino acid peptide designated as BP7, with specific affinity for BNNS, and used it as a linker to load CpG ODNs on BNNS. The tyrosine residue (Y) at the eighth position from the N-terminus played a crucial role in the affinity of BP7 to BNNS. BNNS that bound BP7

Depletion of CpG Dinucleotides in Papillomaviruses and Polyomaviruses: A Role for Divergent Evolutionary Pressures.

Science.gov (United States)

Upadhyay, Mohita; Vivekanandan, Perumal

2015-01-01

Papillomaviruses and polyomaviruses are small ds-DNA viruses infecting a wide-range of vertebrate hosts. Evidence supporting co-evolution of the virus with the host does not fully explain the evolutionary path of papillomaviruses and polyomaviruses. Studies analyzing CpG dinucleotide frequencies in virus genomes have provided interesting insights on virus evolution. CpG dinucleotide depletion has not been extensively studied among papillomaviruses and polyomaviruses. We sought to analyze the relative abundance of dinucleotides and the relative roles of evolutionary pressures in papillomaviruses and polyomaviruses. We studied 127 full-length sequences from papillomaviruses and 56 full-length sequences from polyomaviruses. We analyzed the relative abundance of dinucleotides, effective codon number (ENC), differences in synonymous codon usage. We examined the association, if any, between the extent of CpG dinucleotide depletion and the evolutionary lineage of the infected host. We also investigated the contribution of mutational pressure and translational selection to the evolution of papillomaviruses and polyomaviruses. All papillomaviruses and polyomaviruses are CpG depleted. Interestingly, the evolutionary lineage of the infected host determines the extent of CpG depletion among papillomaviruses and polyomaviruses. CpG dinucleotide depletion was more pronounced among papillomaviruses and polyomaviruses infecting human and other mammals as compared to those infecting birds. Our findings demonstrate that CpG depletion among papillomaviruses is linked to mutational pressure; while CpG depletion among polyomaviruses is linked to translational selection. We also present evidence that suggests methylation of CpG dinucleotides may explain, at least in part, the depletion of CpG dinucleotides among papillomaviruses but not polyomaviruses. The extent of CpG depletion among papillomaviruses and polyomaviruses is linked to the evolutionary lineage of the infected host. Our

CpG methylation differences between neurons and glia are highly conserved from mouse to human.

Science.gov (United States)

Kessler, Noah J; Van Baak, Timothy E; Baker, Maria S; Laritsky, Eleonora; Coarfa, Cristian; Waterland, Robert A

2016-01-15

Understanding epigenetic differences that distinguish neurons and glia is of fundamental importance to the nascent field of neuroepigenetics. A recent study used genome-wide bisulfite sequencing to survey differences in DNA methylation between these two cell types, in both humans and mice. That study minimized the importance of cell type-specific differences in CpG methylation, claiming these are restricted to localized genomic regions, and instead emphasized that widespread and highly conserved differences in non-CpG methylation distinguish neurons and glia. We reanalyzed the data from that study and came to markedly different conclusions. In particular, we found widespread cell type-specific differences in CpG methylation, with a genome-wide tendency for neuronal CpG-hypermethylation punctuated by regions of glia-specific hypermethylation. Alarmingly, our analysis indicated that the majority of genes identified by the primary study as exhibiting cell type-specific CpG methylation differences were misclassified. To verify the accuracy of our analysis, we isolated neuronal and glial DNA from mouse cortex and performed quantitative bisulfite pyrosequencing at nine loci. The pyrosequencing results corroborated our analysis, without exception. Most interestingly, we found that gene-associated neuron vs. glia CpG methylation differences are highly conserved across human and mouse, and are very likely to be functional. In addition to underscoring the importance of independent verification to confirm the conclusions of genome-wide epigenetic analyses, our data indicate that CpG methylation plays a major role in neuroepigenetics, and that the mouse is likely an excellent model in which to study the role of DNA methylation in human neurodevelopment and disease. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

CpG dinucleotide frequencies reveal the role of host methylation capabilities in parvovirus evolution.

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Upadhyay, Mohita; Samal, Jasmine; Kandpal, Manish; Vasaikar, Suhas; Biswas, Banhi; Gomes, James; Vivekanandan, Perumal

2013-12-01

Parvoviruses are rapidly evolving viruses that infect a wide range of hosts, including vertebrates and invertebrates. Extensive methylation of the parvovirus genome has been recently demonstrated. A global pattern of methylation of CpG dinucleotides is seen in vertebrate genomes, compared to "fractional" methylation patterns in invertebrate genomes. It remains unknown if the loss of CpG dinucleotides occurs in all viruses of a given DNA virus family that infect host species spanning across vertebrates and invertebrates. We investigated the link between the extent of CpG dinucleotide depletion among autonomous parvoviruses and the evolutionary lineage of the infected host. We demonstrate major differences in the relative abundance of CpG dinucleotides among autonomous parvoviruses which share similar genome organization and common ancestry, depending on the infected host species. Parvoviruses infecting vertebrate hosts had significantly lower relative abundance of CpG dinucleotides than parvoviruses infecting invertebrate hosts. The strong correlation of CpG dinucleotide depletion with the gain in TpG/CpA dinucleotides and the loss of TpA dinucleotides among parvoviruses suggests a major role for CpG methylation in the evolution of parvoviruses. Our data present evidence that links the relative abundance of CpG dinucleotides in parvoviruses to the methylation capabilities of the infected host. In sum, our findings support a novel perspective of host-driven evolution among autonomous parvoviruses.

Methylated site display (MSD)-AFLP, a sensitive and affordable method for analysis of CpG methylation profiles.

Science.gov (United States)

Aiba, Toshiki; Saito, Toshiyuki; Hayashi, Akiko; Sato, Shinji; Yunokawa, Harunobu; Maruyama, Toru; Fujibuchi, Wataru; Kurita, Hisaka; Tohyama, Chiharu; Ohsako, Seiichiroh

2017-03-09

It has been pointed out that environmental factors or chemicals can cause diseases that are developmental in origin. To detect abnormal epigenetic alterations in DNA methylation, convenient and cost-effective methods are required for such research, in which multiple samples are processed simultaneously. We here present methylated site display (MSD), a unique technique for the preparation of DNA libraries. By combining it with amplified fragment length polymorphism (AFLP) analysis, we developed a new method, MSD-AFLP. Methylated site display libraries consist of only DNAs derived from DNA fragments that are CpG methylated at the 5' end in the original genomic DNA sample. To test the effectiveness of this method, CpG methylation levels in liver, kidney, and hippocampal tissues of mice were compared to examine if MSD-AFLP can detect subtle differences in the levels of tissue-specific differentially methylated CpGs. As a result, many CpG sites suspected to be tissue-specific differentially methylated were detected. Nucleotide sequences adjacent to these methyl-CpG sites were identified and we determined the methylation level by methylation-sensitive restriction endonuclease (MSRE)-PCR analysis to confirm the accuracy of AFLP analysis. The differences of the methylation level among tissues were almost identical among these methods. By MSD-AFLP analysis, we detected many CpGs showing less than 5% statistically significant tissue-specific difference and less than 10% degree of variability. Additionally, MSD-AFLP analysis could be used to identify CpG methylation sites in other organisms including humans. MSD-AFLP analysis can potentially be used to measure slight changes in CpG methylation level. Regarding the remarkable precision, sensitivity, and throughput of MSD-AFLP analysis studies, this method will be advantageous in a variety of epigenetics-based research.

Reproducibility of methylated CpG typing with the Illumina MiSeq

DEFF Research Database (Denmark)

Kampmann, Marie-Louise; Meyer, Olivia Strunge; Greby Schmidt, Suzanne

2017-01-01

DNA methylation patterns may be used for identification of body fluids and for age estimation of human individuals. We evaluated some of the challenges and pitfalls of studying methylated CpG sites. We compared the methylated CpG analysis of two different methods 1) massively parallel sequencing...

Methylation of the estrogen receptor CpG island distinguishes spontaneous and plutonium-induced tumors from nitrosamine-induced lung tumors

Energy Technology Data Exchange (ETDEWEB)

Belinsky, S.A.; Baylin, S.B.; Issa, J.J. [Johns Hopkins Univ., Baltimore, MD (United States)

1995-12-01

CpG islands located in the promoter region of genes constitute one mechanism for regulating transcription. These islands are normally free of methylation, regardless of the expression state of the gene. Hypermethylation of CpG islands, the addition of a methyl group to the internal cytosine within CpG dinucleotides, can cause silencing of a gene. Hypermethylation has been detected as an early event at specific chromosome loci during the development of colon cancer and represents one mechanism used by neoplatic cells to inactivate tumor suppressor genes. Recent studies have demonstrated this mechanism in inactivation of the VHL tumor suppressor gene in 19% of sporadic renal tumors and the p16 {sup INK4a} tumor suppressor gene in 30% of non-small cell lung cancers. A recent report indicates that the estrogen receptor gene could also be inactivated through methylation. In addition, estrogen receptor CpG island methylation arises as a direct function of age in normal colonic mucosa and is present in virtually all colonic tumors. In cultured colon cancer cells, methylation-associated loss of expression of the estrogen receptor gene results in deregulated growth, suggesting a role for the estrogen receptor in colon cancer development. These results provide further evidence that gene silencing through methylation could be a predominant epigenetic mechanism underlying the development of many different types of cancer. The purpose of the current investigation was to determine whether estrogen receptor CpG island methylation is involved in the development of lung cancer. The frequency for methylation of the estrogen receptor CpG island in rodent lung tumors is summarized.

CpG Island Methylator Phenotype in Primary Gastric Carcinoma

OpenAIRE

TOJO Masayuki:筆頭著者; KONISHI Kazuo; YANO Yuichiro; KATAGIRI Atsushi; NOZAWA Hisako; KUBOTA Yutaro; MURAMOTO Takashi; KONDA Kenichi; SHINMURA Kensuke; TAKIMOTO Masafumi; IMAWARI Michio; YOSHIDA Hitoshi

2013-01-01

Gastric cancers (GC) with methylation of multiple CpG islands have a CpG island methylator phenotype (CIMP) and they can have different biological features. The aim of this study was to investigate the DNA methylation status of GCs and its association with their clinicopathological features. We evaluated the methylation status of four genes (MINT1, MINT2, MINT25 and MINT31) in 105 primary GCs using bisulfite-pyrosequencing analysis. We classified tumors as CIMP-high (CIMP-H), CIMP-low (CIMP-L...

CpG oligodeoxynucleotide nanomedicines for the prophylaxis or treatment of cancers, infectious diseases, and allergies.

Science.gov (United States)

Hanagata, Nobutaka

2017-01-01

Unmethylated cytosine-guanine dinucleotide-containing oligodeoxynucleotides (CpG ODNs), which are synthetic agonists of Toll-like receptor 9 (TLR9), activate humoral and cellular immunity and are being developed as vaccine adjuvants to prevent or treat cancers, infectious diseases, and allergies. Free CpG ODNs have been used in many clinical trials implemented to verify their effects. However, recent research has reported that self-assembled CpG ODNs, protein/peptide-CpG ODN conjugates, and nanomaterial-CpG ODN complexes demonstrate higher adjuvant effects than free CpG ODNs, owing to their improved uptake efficiency into cells expressing TLR9. Moreover, protein/peptide-CpG ODN conjugates and nanomaterial-CpG ODN complexes are able to deliver CpG ODNs and antigens (or allergens) to the same types of cells, which enables a higher degree of prophylaxis or therapeutic effect. In this review, the author describes recent trends in the research and development of CpG ODN nanomedicines containing self-assembled CpG ODNs, protein/peptide-CpG ODN conjugates, and nanomaterial-CpG ODN complexes, focusing mainly on the results of preclinical and clinical studies.

CpG methylation controls reactivation of HIV from latency.

Directory of Open Access Journals (Sweden)

Jana Blazkova

2009-08-01

Full Text Available DNA methylation of retroviral promoters and enhancers localized in the provirus 5' long terminal repeat (LTR is considered to be a mechanism of transcriptional suppression that allows retroviruses to evade host immune responses and antiretroviral drugs. However, the role of DNA methylation in the control of HIV-1 latency has never been unambiguously demonstrated, in contrast to the apparent importance of transcriptional interference and chromatin structure, and has never been studied in HIV-1-infected patients. Here, we show in an in vitro model of reactivable latency and in a latent reservoir of HIV-1-infected patients that CpG methylation of the HIV-1 5' LTR is an additional epigenetic restriction mechanism, which controls resistance of latent HIV-1 to reactivation signals and thus determines the stability of the HIV-1 latency. CpG methylation acts as a late event during establishment of HIV-1 latency and is not required for the initial provirus silencing. Indeed, the latent reservoir of some aviremic patients contained high proportions of the non-methylated 5' LTR. The latency controlled solely by transcriptional interference and by chromatin-dependent mechanisms in the absence of significant promoter DNA methylation tends to be leaky and easily reactivable. In the latent reservoir of HIV-1-infected individuals without detectable plasma viremia, we found HIV-1 promoters and enhancers to be hypermethylated and resistant to reactivation, as opposed to the hypomethylated 5' LTR in viremic patients. However, even dense methylation of the HIV-1 5'LTR did not confer complete resistance to reactivation of latent HIV-1 with some histone deacetylase inhibitors, protein kinase C agonists, TNF-alpha, and their combinations with 5-aza-2deoxycytidine: the densely methylated HIV-1 promoter was most efficiently reactivated in virtual absence of T cell activation by suberoylanilide hydroxamic acid. Tight but incomplete control of HIV-1 latency by CpG

Compositional searching of CpG islands in the human genome

Science.gov (United States)

Luque-Escamilla, Pedro Luis; Martínez-Aroza, José; Oliver, José L.; Gómez-Lopera, Juan Francisco; Román-Roldán, Ramón

2005-06-01

We report on an entropic edge detector based on the local calculation of the Jensen-Shannon divergence with application to the search for CpG islands. CpG islands are pieces of the genome related to gene expression and cell differentiation, and thus to cancer formation. Searching for these CpG islands is a major task in genetics and bioinformatics. Some algorithms have been proposed in the literature, based on moving statistics in a sliding window, but its size may greatly influence the results. The local use of Jensen-Shannon divergence is a completely different strategy: the nucleotide composition inside the islands is different from that in their environment, so a statistical distance—the Jensen-Shannon divergence—between the composition of two adjacent windows may be used as a measure of their dissimilarity. Sliding this double window over the entire sequence allows us to segment it compositionally. The fusion of those segments into greater ones that satisfy certain identification criteria must be achieved in order to obtain the definitive results. We find that the local use of Jensen-Shannon divergence is very suitable in processing DNA sequences for searching for compositionally different structures such as CpG islands, as compared to other algorithms in literature.

Reinforcement learning for a biped robot based on a CPG-actor-critic method.

Science.gov (United States)

Nakamura, Yutaka; Mori, Takeshi; Sato, Masa-aki; Ishii, Shin

2007-08-01

Animals' rhythmic movements, such as locomotion, are considered to be controlled by neural circuits called central pattern generators (CPGs), which generate oscillatory signals. Motivated by this biological mechanism, studies have been conducted on the rhythmic movements controlled by CPG. As an autonomous learning framework for a CPG controller, we propose in this article a reinforcement learning method we call the "CPG-actor-critic" method. This method introduces a new architecture to the actor, and its training is roughly based on a stochastic policy gradient algorithm presented recently. We apply this method to an automatic acquisition problem of control for a biped robot. Computer simulations show that training of the CPG can be successfully performed by our method, thus allowing the biped robot to not only walk stably but also adapt to environmental changes.

Transcription of hepatitis B virus covalently closed circular DNA is regulated by CpG methylation during chronic infection.

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Yongmei Zhang

Full Text Available The persistence of hepatitis B virus (HBV infection is maintained by the nuclear viral covalently closed circular DNA (cccDNA, which serves as transcription template for viral mRNAs. Previous studies suggested that cccDNA contains methylation-prone CpG islands, and that the minichromosome structure of cccDNA is epigenetically regulated by DNA methylation. However, the regulatory effect of each CpG island methylation on cccDNA activity remains elusive. In the present study, we analyzed the distribution of CpG methylation within cccDNA in patient samples and investigated the impact of CpG island methylation on cccDNA-driven virus replication. Our study revealed the following observations: 1 Bisulfite sequencing of cccDNA from chronic hepatitis B patients indicated that CpG island I was seldom methylated, 2 CpG island II methylation was correlated to the low level of serum HBV DNA in patients, and in vitro methylation studies confirmed that CpG island II methylation markedly reduced cccDNA transcription and subsequent viral core DNA replication, 3 CpG island III methylation was associated with low serum HBsAg titers, and 4 Furthermore, we found that HBV genotype, HBeAg positivity, and patient age and liver fibrosis stage were also relevant to cccDNA CpG methylation status. Therefore, we clearly demonstrated that the status of cccDNA methylation is connected to the biological behavior of HBV. Taken together, our study provides a complete profile of CpG island methylation within HBV cccDNA and new insights for the function of CpG methylation in regulating HBV cccDNA transcription.

The Use of Chlorhexidine/n-Propyl Gallate (CPG) as an Ambient-Temperature Urine Preservative

Science.gov (United States)

Nillen, Jeannie L.; Smith, Scott M.

2003-01-01

A safe, effective ambient temperature urine preservative, chlorhexidine/n-propyl gallate (CPG), has been formulated for use during spacefli ght that reduces the effects of oxidation and bacterial contamination on sample integrity while maintaining urine pH. The ability of this preservative to maintain stability of nine key analytes was evaluated for a period of one year. CPG effectively maintained stability of a mmonia, total nitrogen, 3-methylhistidine, chloride, sodium, potassiu m, and urea; however, creatinine and osmolality were not preserved by CPG. These data indicate that CPG offers prolonged room-temperature storage for multiple urine analytes, reducing the requirements for f rozen urine storage on future spaceflights. Iii medical applications on Earth, this technology can allow urine samples to be collected in remote settings and eliminate the need to ship frozen samples.

GaussianCpG: a Gaussian model for detection of CpG island in human genome sequences.

Science.gov (United States)

Yu, Ning; Guo, Xuan; Zelikovsky, Alexander; Pan, Yi

2017-05-24

As crucial markers in identifying biological elements and processes in mammalian genomes, CpG islands (CGI) play important roles in DNA methylation, gene regulation, epigenetic inheritance, gene mutation, chromosome inactivation and nuclesome retention. The generally accepted criteria of CGI rely on: (a) %G+C content is ≥ 50%, (b) the ratio of the observed CpG content and the expected CpG content is ≥ 0.6, and (c) the general length of CGI is greater than 200 nucleotides. Most existing computational methods for the prediction of CpG island are programmed on these rules. However, many experimentally verified CpG islands deviate from these artificial criteria. Experiments indicate that in many cases %G+C is human genome. We analyze the energy distribution over genomic primary structure for each CpG site and adopt the parameters from statistics of Human genome. The evaluation results show that the new model can predict CpG islands efficiently by balancing both sensitivity and specificity over known human CGI data sets. Compared with other models, GaussianCpG can achieve better performance in CGI detection. Our Gaussian model aims to simplify the complex interaction between nucleotides. The model is computed not by the linear statistical method but by the Gaussian energy distribution and accumulation. The parameters of Gaussian function are not arbitrarily designated but deliberately chosen by optimizing the biological statistics. By using the pseudopotential analysis on CpG islands, the novel model is validated on both the real and artificial data sets.

CpG island methylator phenotype-low (CIMP-low) colorectal cancer shows not only few methylated CIMP-high-specific CpG islands, but also low-level methylation at individual loci.

Science.gov (United States)

Kawasaki, Takako; Ohnishi, Mutsuko; Nosho, Katsuhiko; Suemoto, Yuko; Kirkner, Gregory J; Meyerhardt, Jeffrey A; Fuchs, Charles S; Ogino, Shuji

2008-03-01

The CpG island methylator phenotype (CIMP or CIMP-high) with widespread promoter methylation is a distinct phenotype in colorectal cancer. However, the concept of CIMP-low with less extensive CpG island methylation is still evolving. Our aim is to examine whether density of methylation in individual CpG islands was different between CIMP-low and CIMP-high tumors. Utilizing MethyLight technology and 889 population-based colorectal cancers, we quantified DNA methylation (methylation index, percentage of methylated reference) at 14 CpG islands, including 8 CIMP-high-specific loci (CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3 and SOCS1). Methylation positivity in each locus was defined as methylation index>4. Low-level methylation (methylation index>0, CIMP-high-specific locus was significantly more common in 340 CIMP-low tumors (1/8-5/8 methylation-positive loci) than 133 CIMP-high tumors (> or =6/8 methylation-positive loci) and 416 CIMP-0 tumors (0/8 methylation-positive loci) (PCIMP-high, low-level methylation, was not persistently more prevalent in CIMP-low tumors. In conclusion, compared to CIMP-high and CIMP-0 tumors, CIMP-low colorectal cancers show not only few methylated CIMP-high-specific CpG islands, but also more frequent low-level methylation at individual loci. Our data may provide supporting evidence for a difference in pathogenesis of DNA methylation between CIMP-low and CIMP-high tumors.

Parvovirus b19 DNA CpG dinucleotide methylation and epigenetic regulation of viral expression.

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Francesca Bonvicini

Full Text Available CpG DNA methylation is one of the main epigenetic modifications playing a role in the control of gene expression. For DNA viruses whose genome has the ability to integrate in the host genome or to maintain as a latent episome, a correlation has been found between the extent of DNA methylation and viral quiescence. No information is available for Parvovirus B19, a human pathogenic virus, which is capable of both lytic and persistent infections. Within Parvovirus B19 genome, the inverted terminal regions display all the characteristic signatures of a genomic CpG island; therefore we hypothesised a role of CpG dinucleotide methylation in the regulation of viral genome expression.The analysis of CpG dinucleotide methylation of Parvovirus B19 DNA was carried out by an aptly designed quantitative real-time PCR assay on bisulfite-modified DNA. The effects of CpG methylation on the regulation of viral genome expression were first investigated by transfection of either unmethylated or in vitro methylated viral DNA in a model cell line, showing that methylation of viral DNA was correlated to lower expression levels of the viral genome. Then, in the course of in vitro infections in different cellular environments, it was observed that absence of viral expression and genome replication were both correlated to increasing levels of CpG methylation of viral DNA. Finally, the presence of CpG methylation was documented in viral DNA present in bioptic samples, indicating the occurrence and a possible role of this epigenetic modification in the course of natural infections.The presence of an epigenetic level of regulation of viral genome expression, possibly correlated to the silencing of the viral genome and contributing to the maintenance of the virus in tissues, can be relevant to the balance and outcome of the different types of infection associated to Parvovirus B19.

Parvovirus B19 DNA CpG Dinucleotide Methylation and Epigenetic Regulation of Viral Expression

Science.gov (United States)

Bonvicini, Francesca; Manaresi, Elisabetta; Di Furio, Francesca; De Falco, Luisa; Gallinella, Giorgio

2012-01-01

CpG DNA methylation is one of the main epigenetic modifications playing a role in the control of gene expression. For DNA viruses whose genome has the ability to integrate in the host genome or to maintain as a latent episome, a correlation has been found between the extent of DNA methylation and viral quiescence. No information is available for Parvovirus B19, a human pathogenic virus, which is capable of both lytic and persistent infections. Within Parvovirus B19 genome, the inverted terminal regions display all the characteristic signatures of a genomic CpG island; therefore we hypothesised a role of CpG dinucleotide methylation in the regulation of viral genome expression. The analysis of CpG dinucleotide methylation of Parvovirus B19 DNA was carried out by an aptly designed quantitative real-time PCR assay on bisulfite-modified DNA. The effects of CpG methylation on the regulation of viral genome expression were first investigated by transfection of either unmethylated or in vitro methylated viral DNA in a model cell line, showing that methylation of viral DNA was correlated to lower expression levels of the viral genome. Then, in the course of in vitro infections in different cellular environments, it was observed that absence of viral expression and genome replication were both correlated to increasing levels of CpG methylation of viral DNA. Finally, the presence of CpG methylation was documented in viral DNA present in bioptic samples, indicating the occurrence and a possible role of this epigenetic modification in the course of natural infections. The presence of an epigenetic level of regulation of viral genome expression, possibly correlated to the silencing of the viral genome and contributing to the maintenance of the virus in tissues, can be relevant to the balance and outcome of the different types of infection associated to Parvovirus B19. PMID:22413013

Physiological, anatomical and genetic identification of CPG neurons in the developing mammalian spinal cord

DEFF Research Database (Denmark)

Kiehn, Ole; Butt, Simon J.B.

2003-01-01

. These latter experiments have defined EphA4 as a molecular marker for mammalian excitatory hindlimb CPG neurons. We also review genetic approaches that can be applied to the mouse spinal cord. These include methods for identifying sub-populations of neurons by genetically encoded reporters, techniques to trace...... network connectivity with cell-specific genetically encoded tracers, and ways to selectively ablate or eliminate neuron populations from the CPG. We propose that by applying a multidisciplinary approach it will be possible to understand the network structure of the mammalian locomotor CPG...

Integrated analysis of gene expression, CpG island methylation, and gene copy number in breast cancer cells by deep sequencing.

Directory of Open Access Journals (Sweden)

Zhifu Sun

Full Text Available We used deep sequencing technology to profile the transcriptome, gene copy number, and CpG island methylation status simultaneously in eight commonly used breast cell lines to develop a model for how these genomic features are integrated in estrogen receptor positive (ER+ and negative breast cancer. Total mRNA sequence, gene copy number, and genomic CpG island methylation were carried out using the Illumina Genome Analyzer. Sequences were mapped to the human genome to obtain digitized gene expression data, DNA copy number in reference to the non-tumor cell line (MCF10A, and methylation status of 21,570 CpG islands to identify differentially expressed genes that were correlated with methylation or copy number changes. These were evaluated in a dataset from 129 primary breast tumors. Gene expression in cell lines was dominated by ER-associated genes. ER+ and ER- cell lines formed two distinct, stable clusters, and 1,873 genes were differentially expressed in the two groups. Part of chromosome 8 was deleted in all ER- cells and part of chromosome 17 amplified in all ER+ cells. These loci encoded 30 genes that were overexpressed in ER+ cells; 9 of these genes were overexpressed in ER+ tumors. We identified 149 differentially expressed genes that exhibited differential methylation of one or more CpG islands within 5 kb of the 5' end of the gene and for which mRNA abundance was inversely correlated with CpG island methylation status. In primary tumors we identified 84 genes that appear to be robust components of the methylation signature that we identified in ER+ cell lines. Our analyses reveal a global pattern of differential CpG island methylation that contributes to the transcriptome landscape of ER+ and ER- breast cancer cells and tumors. The role of gene amplification/deletion appears to more modest, although several potentially significant genes appear to be regulated by copy number aberrations.

Synergy of anti-CD40, CpG and MPL in activation of mouse macrophages.

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Shi, Yongyu; Felder, Mildred A R; Sondel, Paul M; Rakhmilevich, Alexander L

2015-08-01

Activation of macrophages is a prerequisite for their antitumor effects. Several reagents, including agonistic anti-CD40 monoclonal antibody (anti-CD40), CpG oligodeoxynucleotides (CpG) and monophosphoryl lipid A (MPL), can stimulate activation of macrophages. Our previous studies showed synergy between anti-CD40 and CpG and between anti-CD40 and MPL in macrophage activation and antitumor efficacy in mice. In the present study, we asked whether there was synergy among these three reagents. The activation of adherent peritoneal exudate cells (PEC) obtained from mice injected with anti-CD40 and then treated with CpG and/or MPL in vitro was determined by their ability to suppress proliferation of tumor cells and to produce various cytokines and chemokines in vitro. Cell sorting and histology followed by functional testing showed that macrophages were the main cell population in PEC activated by CD40 ligation in vivo. A combination of anti-CD40, CpG or MPL activated PEC to suppress proliferation of B16 cells and produce nitric oxide far greater than the single reagents or any of the double combinations of these reagents. In addition, the combination of all three reagents activated PEC to secrete IL-12, IFN-γ and MCP-1 to a greater degree than any single reagent or any two combined reagents. These results demonstrate that macrophages can be synergistically activated by anti-CD40, CpG and MPL, suggesting that this novel combined approach might be further investigated as potential cancer therapy. Copyright © 2015 Elsevier Ltd. All rights reserved.

Synergy of anti-CD40, CpG and MPL in activation of mouse macrophages

Science.gov (United States)

Shi, Yongyu; Felder, Mildred A.R.; Sondel, Paul M.; Rakhmilevich, Alexander L.

2015-01-01

Activation of macrophages is a prerequisite for their antitumor effects. Several reagents, including agonistic anti-CD40 monoclonal antibody (anti-CD40), CpG oligodeoxynucleotides (CpG) and monophosphoryl lipid A (MPL), can stimulate activation of macrophages. Our previous studies showed synergy between anti-CD40 and CpG and between anti-CD40 and MPL in macrophage activation and antitumor efficacy in mice. In the present study, we asked whether there was synergy among these three reagents. The activation of adherent peritoneal exudate cells (PEC) obtained from mice injected with anti-CD40 and then treated with CpG and/or MPL in vitro was determined by their ability to suppress proliferation of tumor cells and to produce various cytokines and chemokines in vitro. Cell sorting and histology followed by functional testing showed that macrophages were the main cell population in PEC activated by CD40 ligation in vivo. A combination of anti-CD40, CpG or MPL activated PEC to suppress proliferation of B16 cells and produce nitric oxide far greater than the single reagents or any of the double combinations of these reagents. In addition, the combination of all three reagents activated PEC to secrete IL-12, IFN-γ and MCP-1 to a greater degree than any single reagent or any two combined reagents. These results demonstrate that macrophages can be synergistically activated by anti-CD40, CpG and MPL, suggesting that this novel combined approach might be further investigated as potential cancer therapy. PMID:25829245

Endogenous sunk costs and the geographic differences in the market structures of CPG Categories

NARCIS (Netherlands)

Bronnenberg, B.J.; Dhar, S.; Dube, J.P.

2011-01-01

We describe the industrial market structure of CPG categories. The analysis uses a unique database spanning 31 consumer package goods (CPG) categories, 39 months, and the 50 largest US metropolitan markets. We organize our description of market structure around the notion that firms can improve

A CpG oligonucleotide can protect mice from a low aerosol challenge dose of Burkholderia mallei.

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Waag, David M; McCluskie, Michael J; Zhang, Ningli; Krieg, Arthur M

2006-03-01

Treatment with an oligodeoxynucleotide (ODN) containing CPG motifs (CpG ODN 7909) was found to protect BALB/c mice from lung infection or death after aerosol challenge with Burkholderia mallei. Protection was associated with enhanced levels of gamma interferon (IFN-gamma)-inducible protein 10, interleukin-12 (IL-12), IFN-gamma, and IL-6. Preexposure therapy with CpG ODNs may protect victims of a biological attack from glanders.

Phase 1 trial of the Plasmodium falciparum blood stage vaccine MSP1(42-C1/Alhydrogel with and without CPG 7909 in malaria naïve adults.

Directory of Open Access Journals (Sweden)

Ruth D Ellis

2010-01-01

Full Text Available Merozoite surface protein 1(42 (MSP1(42 is a leading blood stage malaria vaccine candidate. In order to induce immune responses that cover the major antigenic polymorphisms, FVO and 3D7 recombinant proteins of MSP1(42 were mixed (MSP1(42-C1. To improve the level of antibody response, MSP1(42-C1 was formulated with Alhydrogel plus the novel adjuvant CPG 7909.A Phase 1 clinical trial was conducted in healthy malaria-naïve adults at the Center for Immunization Research in Washington, D.C., to evaluate the safety and immunogenicity of MSP1(42-C1/Alhydrogel +/- CPG 7909. Sixty volunteers were enrolled in dose escalating cohorts and randomized to receive three vaccinations of either 40 or 160 microg protein adsorbed to Alhydrogel +/- 560 microg CPG 7909 at 0, 1 and 2 months.Vaccinations were well tolerated, with only one related adverse event graded as severe (Grade 3 injection site erythema and all other vaccine related adverse events graded as either mild or moderate. Local adverse events were more frequent and severe in the groups receiving CPG. The addition of CPG enhanced anti-MSP1(42 antibody responses following vaccination by up to 49-fold two weeks after second immunization and 8-fold two weeks after the third immunization when compared to MSP1(42-C1/Alhydrogel alone (p<0.0001. After the third immunization, functionality of the antibody was tested by an in vitro growth inhibition assay. Inhibition was a function of antibody titer, with an average of 3% (range -2 to 10% in the non CPG groups versus 14% (3 to 32% in the CPG groups.The favorable safety profile and high antibody responses induced with MSP1(42-C1/Alhydrogel + CPG 7909 are encouraging. MSP1(42-C1/Alhydrogel is being combined with other blood stage antigens and will be taken forward in a formulation adjuvanted with CPG 7909.ClinicalTrials.gov Identifier: NCT00320658.

Polycomb-like proteins link the PRC2 complex to CpG islands

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Li, Haojie; Liefke, Robert; Jiang, Junyi; Kurland, Jesse Vigoda; Tian, Wei; Deng, Pujuan; Zhang, Weidi; He, Qian; Patel, Dinshaw J.; Bulyk, Martha L.; Shi, Yang; Wang, Zhanxin

2017-09-06

The Polycomb repressive complex 2 (PRC2) mainly mediates transcriptional repression1,2 and has essential roles in various biological processes including the maintenance of cell identity and proper differentiation. Polycomb-like (PCL) proteins, such as PHF1, MTF2 and PHF19, are PRC2-associated factors that form sub-complexes with PRC2 core components3, and have been proposed to modulate the enzymatic activity of PRC2 or the recruitment of PRC2 to specific genomic loci4,5,6,7,8,9,10,11,12,13. Mammalian PRC2-binding sites are enriched in CG content, which correlates with CpG islands that display a low level of DNA methylation14. However, the mechanism of PRC2 recruitment to CpG islands is not fully understood. Here we solve the crystal structures of the N-terminal domains of PHF1 and MTF2 with bound CpG-containing DNAs in the presence of H3K36me3-containing histone peptides. We show that the extended homologous regions of both proteins fold into a winged-helix structure, which specifically binds to the unmethylated CpG motif but in a completely different manner from the canonical winged-helix DNA recognition motif. We also show that the PCL extended homologous domains are required for efficient recruitment of PRC2 to CpG island-containing promoters in mouse embryonic stem cells. Our research provides the first, to our knowledge, direct evidence to demonstrate that PCL proteins are crucial for PRC2 recruitment to CpG islands, and further clarifies the roles of these proteins in transcriptional regulation in vivo.

Glutamatergic mechanisms for speed control and network operation in the rodent locomotor CPG

DEFF Research Database (Denmark)

Talpalar, Adolfo E.; Kiehn, Ole

2010-01-01

in mammals have produced conflicting results regarding the necessity and role of the different ionotropic glutamate receptors (GluRs) in the CPG function. Here, we use electrophysiological and pharmacological techniques in the in vitro neonatal mouse lumbar spinal cord to investigate the role of a broad...... mechanisms acting at various network levels. AMPA and kainate receptors are necessary for generating the highest locomotor frequencies. For coordination, NMDARs are more important than non-NMDARs for conveying the rhythmic signal from the network to the motor neurons during long-lasting and steady locomotor...

The effect of TLR9 agonist CpG oligodeoxynucleotides on the intestinal immune response of cobia (Rachycentron canadum).

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Byadgi, Omkar; Puteri, Dinda; Lee, Jai-Wei; Chang, Tsung-Chou; Lee, Yan-Horn; Chu, Chun-Yen; Cheng, Ta-Chih

2014-01-01

Cytosine-guanine oligodeoxynucleotide (CpG ODN) motifs of bacterial DNA are recognized through toll-like receptor 9 (TLR9) and are potent activators of innate immunity. However, the interaction between TLR9 and CpG ODN in aquatic species has not been well characterized. Hence, cobia TLR9 isoform B (RCTLR9B) was cloned and its expression and induction in intestine were investigated. RCTLR9B cDNA consists of 3113bp encoding 1009 amino acids containing three regions, leucine rich repeats, transmembrane domain, and toll/interleukin-1 receptor (TIR) domain. Intraperitoneal injection of CpG ODN 2395 upregulated RCTLR9 A and B and MyD88 and also induced the expressions of Mx, chemokine CC, and interleukin IL-1 β . Cobia intraperitoneally injected with CpG ODN 1668 and 2395 had increased survival rates after challenge with Photobacterium damselae subsp. piscicida. In addition, formulation of CpG ODN with formalin-killed bacteria (FKB) and aluminum hydroxide gel significantly increased expressions of RCTLR9 A (50 folds) and B (30 folds) isoforms at 10 dpi (CpG ODN 1668) and MyD88 (21 folds) at 6 dpv (CpG ODN 2395). Subsequently, IL-1 β increased at 6 dpv in 1668 group. No histopathological damage and inflammatory responses were observed in the injected cobia. Altogether, these results facilitate CpG ODNs as an adjuvant to increase bacterial disease resistance and efficacy of vaccines in cobia.

The Effect of TLR9 Agonist CpG Oligodeoxynucleotides on the Intestinal Immune Response of Cobia (Rachycentron canadum

Directory of Open Access Journals (Sweden)

Omkar Byadgi

2014-01-01

Full Text Available Cytosine-guanine oligodeoxynucleotide (CpG ODN motifs of bacterial DNA are recognized through toll-like receptor 9 (TLR9 and are potent activators of innate immunity. However, the interaction between TLR9 and CpG ODN in aquatic species has not been well characterized. Hence, cobia TLR9 isoform B (RCTLR9B was cloned and its expression and induction in intestine were investigated. RCTLR9B cDNA consists of 3113bp encoding 1009 amino acids containing three regions, leucine rich repeats, transmembrane domain, and toll/interleukin-1 receptor (TIR domain. Intraperitoneal injection of CpG ODN 2395 upregulated RCTLR9 A and B and MyD88 and also induced the expressions of Mx, chemokine CC, and interleukin IL-1β. Cobia intraperitoneally injected with CpG ODN 1668 and 2395 had increased survival rates after challenge with Photobacterium damselae subsp. piscicida. In addition, formulation of CpG ODN with formalin-killed bacteria (FKB and aluminum hydroxide gel significantly increased expressions of RCTLR9 A (50 folds and B (30 folds isoforms at 10 dpi (CpG ODN 1668 and MyD88 (21 folds at 6 dpv (CpG ODN 2395. Subsequently, IL-1β increased at 6 dpv in 1668 group. No histopathological damage and inflammatory responses were observed in the injected cobia. Altogether, these results facilitate CpG ODNs as an adjuvant to increase bacterial disease resistance and efficacy of vaccines in cobia.

Protective immunity against Megalocytivirus infection in rock bream (Oplegnathus fasciatus) following CpG ODN administration.

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Jung, Myung-Hwa; Lee, Jehee; Ortega-Villaizan, M; Perez, Luis; Jung, Sung-Ju

2017-06-27

Rock bream iridovirus (RBIV) disease in rock bream (Oplegnathus fasciatus) remains an unsolved problem in Korea aquaculture farms. CpG ODNs are known as immunostimulant, can improve the innate immune system of fish providing resistance to diseases. In this study, we evaluated the potential of CpG ODNs to induce anti-viral status protecting rock bream from different RBIV infection conditions. We found that, when administered into rock bream, CpG ODN 1668 induces better antiviral immune responses compared to other 5 CpG ODNs (2216, 1826, 2133, 2395 and 1720). All CpG ODN 1668 administered fish (1/5µg) at 2days before infection (1.1×10 7 ) held at 26°C died even though mortality was delayed from 8days (1µg) and 4days (5µg). Similarly, CpG ODN 1668 administered (5µg) at 2days before infection (1.2×10 6 ) held at 23/20°C had 100% mortality; the mortality was delayed from 9days (23°C) and 11days (20°C). Moreover, when CpG ODN 1668 administered (1/5/10µg) at 2/4/7days before infection or virus concentration was decreased to 1.1×10 4 and held at 20°C had mortality rates of 20/60/30% (2days), 30/40/60% (4days) and 60/60/20% (7days), respectively, for the respective administration dose, through 100 dpi. To investigate the development of a protective immune response, survivors were re-infected with RBIV (1.1×10 7 ) at 100 and 400 dpi, respectively. While 100% of the previously unexposed fish died, 100% of the previously infected fish survived. The high survival rate of fish following re-challenge with RBIV indicates that protective immunity was established in the surviving rock bream. Our results showed the possibility of developing preventive measures against RBIV using CpG ODN 1668 by reducing RBIV replication speed (i.e. water temperature of 20°C and infection dose of 1.1×10 4 ). Copyright © 2017 Elsevier Ltd. All rights reserved.

Protection of Balb/c mice against infection with FMDV by immunostimulation with CpG oligonucleotides

DEFF Research Database (Denmark)

Kamstrup, Søren; Frimann, Tine; Barfoed, Annette Malene

2006-01-01

disease virus (FMDV). Susceptibility of Balb/c mice to infection with isolates from the different serotypes of FMDV was investigated, and, at the same time, the capacity of CpG ODN to modulate the infection was evaluated. Treatment with CpG significantly reduced viremia, disease and death in five of six...... serotypes, when compared to no treatment or treatment with a control ODN. The effect was observed when ODN was administered simultaneously with, or up to 12 h after, infection with FMDV, and lasted for 14 days post treatment. The potential application of CpG ODN for control of FMDV during an outbreak...

CpG oligodeoxyribonucleotides protect mice from Burkholderia pseudomallei but not Francisella tularensis Schu S4 aerosols.

Science.gov (United States)

Rozak, David A; Gelhaus, Herbert C; Smith, Mark; Zadeh, Mojgan; Huzella, Louis; Waag, David; Adamovicz, Jeffrey J

2010-02-05

Studies have shown that CpG oligodeoxyribonucleotides (ODN) protect mice from various bacterial pathogens, including Burkholderia pseudomallei and Francisella tularensis live vaccine strain (LVS), when administered before parenteral challenge. Given the potential to develop CpG ODN as a pre-treatment for multiple bacterial biological warfare agents, we examined survival, histopathology, and cytokine data from CpG ODN-treated C57BL/6 mice to determine whether previously-reported protection extended to aerosolized B. pseudomallei 1026b and highly virulent F. tularensis Schu S4 infections. We found that, although CpG ODN protected mice from aerosolized B. pseudomallei challenges, the immunostimulant failed to benefit the animals exposed to F. tularensis Schu S4 aerosols. Our results, which contrast with earlier F. tularensis LVS studies, highlight potential differences in Francisella species pathogenesis and underscore the need to evaluate immunotherapies against human pathogenic species.

A genome-wide methylation study on obesity: differential variability and differential methylation.

Science.gov (United States)

Xu, Xiaojing; Su, Shaoyong; Barnes, Vernon A; De Miguel, Carmen; Pollock, Jennifer; Ownby, Dennis; Shi, Hidong; Zhu, Haidong; Snieder, Harold; Wang, Xiaoling

2013-05-01

Besides differential methylation, DNA methylation variation has recently been proposed and demonstrated to be a potential contributing factor to cancer risk. Here we aim to examine whether differential variability in methylation is also an important feature of obesity, a typical non-malignant common complex disease. We analyzed genome-wide methylation profiles of over 470,000 CpGs in peripheral blood samples from 48 obese and 48 lean African-American youth aged 14-20 y old. A substantial number of differentially variable CpG sites (DVCs), using statistics based on variances, as well as a substantial number of differentially methylated CpG sites (DMCs), using statistics based on means, were identified. Similar to the findings in cancers, DVCs generally exhibited an outlier structure and were more variable in cases than in controls. By randomly splitting the current sample into a discovery and validation set, we observed that both the DVCs and DMCs identified from the first set could independently predict obesity status in the second set. Furthermore, both the genes harboring DMCs and the genes harboring DVCs showed significant enrichment of genes identified by genome-wide association studies on obesity and related diseases, such as hypertension, dyslipidemia, type 2 diabetes and certain types of cancers, supporting their roles in the etiology and pathogenesis of obesity. We generalized the recent finding on methylation variability in cancer research to obesity and demonstrated that differential variability is also an important feature of obesity-related methylation changes. Future studies on the epigenetics of obesity will benefit from both statistics based on means and statistics based on variances.

Humanoids Learning to Walk: A Natural CPG-Actor-Critic Architecture.

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Li, Cai; Lowe, Robert; Ziemke, Tom

2013-01-01

The identification of learning mechanisms for locomotion has been the subject of much research for some time but many challenges remain. Dynamic systems theory (DST) offers a novel approach to humanoid learning through environmental interaction. Reinforcement learning (RL) has offered a promising method to adaptively link the dynamic system to the environment it interacts with via a reward-based value system. In this paper, we propose a model that integrates the above perspectives and applies it to the case of a humanoid (NAO) robot learning to walk the ability of which emerges from its value-based interaction with the environment. In the model, a simplified central pattern generator (CPG) architecture inspired by neuroscientific research and DST is integrated with an actor-critic approach to RL (cpg-actor-critic). In the cpg-actor-critic architecture, least-square-temporal-difference based learning converges to the optimal solution quickly by using natural gradient learning and balancing exploration and exploitation. Futhermore, rather than using a traditional (designer-specified) reward it uses a dynamic value function as a stability indicator that adapts to the environment. The results obtained are analyzed using a novel DST-based embodied cognition approach. Learning to walk, from this perspective, is a process of integrating levels of sensorimotor activity and value.

Humanoids Learning to Walk: a Natural CPG-Actor-Critic Architecture

Directory of Open Access Journals (Sweden)

CAI eLI

2013-04-01

Full Text Available The identification of learning mechanisms for locomotion has been the subject of much researchfor some time but many challenges remain. Dynamic systems theory (DST offers a novel approach to humanoid learning through environmental interaction. Reinforcement learning (RL has offered a promising method to adaptively link the dynamic system to the environment it interacts with via a reward-based value system.In this paper, we propose a model that integrates the above perspectives and applies it to the case of a humanoid (NAO robot learning to walk the ability of which emerges from its value-based interaction with the environment. In the model,a simplified central pattern generator (CPG architecture inspired by neuroscientific research and DST is integrated with an actor-critic approach to RL (cpg-actor-critic. In the cpg-actor-critic architecture, least-square-temporal-difference (LSTD based learning converges to the optimal solution quickly by using natural gradient and balancing exploration and exploitation. Futhermore, rather than using a traditional (designer-specified reward it uses a dynamic value function as a stability indicator (SI that adapts to the environment.The results obtained are analyzed and explained by using a novel DST embodied cognition approach. Learning to walk, from this perspective, is a process of integrating sensorimotor levels and value.

Characterization of Immune Responses to an Inactivated Avian Influenza Virus Vaccine Adjuvanted with Nanoparticles Containing CpG ODN.

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Singh, Shirene M; Alkie, Tamiru N; Abdelaziz, Khaled Taha; Hodgins, Douglas C; Novy, Anastasia; Nagy, Éva; Sharif, Shayan

2016-06-01

Avian influenza virus (AIV), a mucosal pathogen, gains entry into host chickens through respiratory and gastrointestinal routes. Most commercial AIV vaccines for poultry consist of inactivated, whole virus with adjuvant, delivered by parenteral administration. Recent advances in vaccine development have led to the application of nanoparticle emulsion delivery systems, such as poly (d,l-lactic-co-glycolic acid) (PLGA) nanoparticles to enhance antigen-specific immune responses. In chickens, the Toll-like receptor 21 ligand, CpG oligodeoxynucleotides (ODNs), have been demonstrated to be immunostimulatory. The objective of this study was to compare the adjuvant potential of CpG ODN 2007 encapsulated in PLGA nanoparticles with nonencapsulated CpG ODN 2007 when combined with a formalin-inactivated H9N2 virus, through intramuscular and aerosol delivery routes. Chickens were vaccinated at days 7 and 21 posthatch for the intramuscular route and at days 7, 21, and 35 for the aerosol route. Antibody-mediated responses were evaluated weekly in sera and lacrimal secretions in specific pathogen-free chickens. The results indicate that nonencapsulated CpG ODN 2007 in inactivated AIV vaccines administered by the intramuscular route generated higher antibody responses compared to the encapsulated CpG ODN 2007 formulation by the same route. Additionally, encapsulated CpG ODN 2007 in AIV vaccines administered by the aerosol route elicited higher mucosal responses compared to nonencapsulated CpG ODN 2007. Future studies may be aimed at evaluating protective immune responses induced with PLGA encapsulation of AIV and adjuvants.

Smooth transition for CPG-based body shape control of a snake-like robot

International Nuclear Information System (INIS)

Nor, Norzalilah Mohamad; Ma, Shugen

2014-01-01

This paper presents a locomotion control based on central pattern generator (CPG) of a snake-like robot. The main point addressed in this paper is a method that produces a smooth transition of the body shape of a snake-like robot. Body shape transition is important for snake-like robot locomotion to adapt to different space widths and also for obstacle avoidance. By manipulating the phase difference of the CPG outputs instantly, it will results in a sharp point or discontinuity which lead to an unstable movement of the snake-like robot. To tackle the problem, we propose a way of controlling the body shape: by incorporating activation function in the phase oscillator CPG model. The simplicity of the method promises an easy implementation and simple control. Simulation results and torque analysis confirm the effectiveness of the proposed control method and thus, can be used as a locomotion control in various potential applications of a snake-like robot. (paper)

CpG island methylator phenotype (CIMP) in cancer: causes and implications.

Science.gov (United States)

Teodoridis, Jens M; Hardie, Catriona; Brown, Robert

2008-09-18

Strong evidence exists for a subgroup of tumours, from a variety of tissue types, exhibiting concordant tumour specific DNA methylation: the "CpG island methylator phenotype" (CIMP). Occurrence of CIMP is associated with a range of genetic and environmental factors, although the molecular causes are not well-understood. Both increased expression and aberrant targeting of DNA methyltransferases (DNMTs) could contribute to the occurrence of CIMP. One under-explored area is the possibility that DNA damage may induce or select for CIMP during carcinogenesis or treatment of tumours with chemotherapy. DNA damaging agents can induce DNA damage at guanine rich regions throughout the genome, including CpG islands. This DNA damage can result in stalled DNA synthesis, which will lead to localised increased DNMT1 concentration and therefore potentially increased DNA methylation at these sites. Chemotherapy can select for cells which have increased tolerance to DNA damage due to increased lesion bypass, in some cases by mechanisms which involve inactivation of genes by CpG island methylation. CIMP has been associated with worse patient prognosis, probably due to increased epigenetic plasticity. Therefore, further clinical testing of the diagnostic and prognostic value of the current CIMP markers, as well as increasing our understanding of the molecular causes underlying CIMP are required.

Dualism of gene GC content and CpG pattern in regard to expression in the human genome: magnitude versus breadth.

Science.gov (United States)

Vinogradov, Alexander E

2005-12-01

In this article, I show that, in the human genome, the GC content in genes (but not the CpG island in the promoter) is related to the maximum level of gene expression among tissues, whereas the promoter CpG island and gene CpG level are more strongly related to the breadth of expression among tissues. The relevance of gene GC content to expression cannot be a consequence (i.e. a byproduct) of transcription because it does not correlate with expression in the germline. The variation of GC content and CpG level can determine the characteristics of gene expression in a synergistic interplay with transcription-factor-binding sites (mediated by chromatin condensation).

Casino Self- and Forced Excluders' Gambling Behavior Before and After Exclusion.

Science.gov (United States)

Kotter, Roxana; Kräplin, Anja; Bühringer, Gerhard

2018-06-01

Casino exclusion programs are intended to prevent or limit gambling-related harm. Although previous research showed that self-exclusion is associated with reduced gambling, it remains unknown whether self- and forced excluded subjects show different patterns of gambling behavior and if exclusion from casino gambling affects all gambling activities. The present study retrospectively investigated (1) the role of voluntariness of exclusion for the first time, and (2) general gambling behavior of excluded individuals before and after exclusion. A total of N = 215 casino excluders (self-excluders: n = 187, forced excluders: n = 28) completed an online survey or a face-to-face interview up to 8 years after enrollment. Self- and forced excluders showed similar rates of abstinence (self-excluders: 19.3%, forced excluders: 28.6%) and reduction (self-excluders: 67.4%, forced excluders: 60.7%), even though forced excluders reported a significantly greater initial gambling intensity compared to self-excluders (e.g., pre-exclusion gambling time; self-excluders: 3.2 days/week, forced excluders: 4.3 days/week). Overall, results indicated that 20.5% of excluders stopped all gambling activities and another 66.5% reduced their gambling. Those who continued gambling significantly reduced this behavior in every segment, except for gambling halls. Findings indicate that self- and forced exclusion are associated with similarly reduced gambling behavior, even in non-excluded segments. However, unchanged gambling in gambling halls emphasizes the importance to implement consistent exclusion programs over all gambling segments.

CpG preconditioning regulates miRNA expression that modulates genomic reprogramming associated with neuroprotection against ischemic injury

Science.gov (United States)

Vartanian, Keri B; Mitchell, Hugh D; Stevens, Susan L; Conrad, Valerie K; McDermott, Jason E; Stenzel-Poore, Mary P

2015-01-01

Cytosine-phosphate-guanine (CpG) preconditioning reprograms the genomic response to stroke to protect the brain against ischemic injury. The mechanisms underlying genomic reprogramming are incompletely understood. MicroRNAs (miRNAs) regulate gene expression; however, their role in modulating gene responses produced by CpG preconditioning is unknown. We evaluated brain miRNA expression in response to CpG preconditioning before and after stroke using microarray. Importantly, we have data from previous gene microarrays under the same conditions, which allowed integration of miRNA and gene expression data to specifically identify regulated miRNA gene targets. CpG preconditioning did not significantly alter miRNA expression before stroke, indicating that miRNA regulation is not critical for the initiation of preconditioning-induced neuroprotection. However, after stroke, differentially regulated miRNAs between CpG- and saline-treated animals associated with the upregulation of several neuroprotective genes, implicating these miRNAs in genomic reprogramming that increases neuroprotection. Statistical analysis revealed that the miRNA targets were enriched in the gene population regulated in the setting of stroke, implying that miRNAs likely orchestrate this gene expression. These data suggest that miRNAs regulate endogenous responses to stroke and that manipulation of these miRNAs may have the potential to acutely activate novel neuroprotective processes that reduce damage. PMID:25388675

Consolidated Recovered Materials Advisory Notice (RMAN) for the Comprehensive Procurement Guideline (CPG)

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U.S. Environmental Protection Agency — EPA's Comprehensive Procurement Guideline (CPG) designates recycled content products that government agencies should buy. EPA publishes purchasing guidance and...

Excluding joint probabilities from quantum theory

Science.gov (United States)

Allahverdyan, Armen E.; Danageozian, Arshag

2018-03-01

Quantum theory does not provide a unique definition for the joint probability of two noncommuting observables, which is the next important question after the Born's probability for a single observable. Instead, various definitions were suggested, e.g., via quasiprobabilities or via hidden-variable theories. After reviewing open issues of the joint probability, we relate it to quantum imprecise probabilities, which are noncontextual and are consistent with all constraints expected from a quantum probability. We study two noncommuting observables in a two-dimensional Hilbert space and show that there is no precise joint probability that applies for any quantum state and is consistent with imprecise probabilities. This contrasts with theorems by Bell and Kochen-Specker that exclude joint probabilities for more than two noncommuting observables, in Hilbert space with dimension larger than two. If measurement contexts are included into the definition, joint probabilities are not excluded anymore, but they are still constrained by imprecise probabilities.

A crucial role for plasmacytoid dendritic cells in antiviral protection by CpG ODN–based vaginal microbicide

Science.gov (United States)

Shen, Hong; Iwasaki, Akiko

2006-01-01

Topical microbicides represent a promising new approach to preventing HIV and other sexually transmitted infections. TLR agonists are ideal candidates for microbicides, as they trigger a multitude of antiviral genes effective against a broad range of viruses. Although vaginal application of CpG oligodeoxynucleotides (ODNs) and poly I:C has been shown to protect mice from genital herpes infection, the mechanism by which these agents provide protection remains unclear. Here, we show that plasmacytoid DCs (pDCs) are required for CpG ODN–mediated protection against lethal vaginal challenge with herpes simplex virus type 2 (HSV-2). Moreover, we demonstrate that cells of both the hematopoietic and stromal compartments must respond to CpG ODN via TLR9 and to type I IFNs through IFN-αβ receptor (IFN-αβR) for protection. Thus, crosstalk between pDCs and vaginal stromal cells provides for optimal microbicide efficacy. Our results imply that temporally and spatially controlled targeting of CpG ODN to pDCs and epithelial cells can potentially maximize their effectiveness as microbicides while minimizing the associated inflammatory responses. PMID:16878177

Fine mapping of the EDA gene: A translocation breakpoint is associated with a CpG island that is transcribed

Energy Technology Data Exchange (ETDEWEB)

Srivastava, A.K.; Schlessinger, D. [Washington Univ. School of Medicine, St. Louis, MO (United States); Montonen, O. [Univ. of Helsinki (Finland)] [and others

1996-01-01

In order to identify the gene for human X-linked anhidrotic ectodermal dysplasia (EDA), a translocation breakpoint in a female with t(X;1)(q13.1;p36.3) and EDA (patient AK) was finely mapped. The EDA region contains five groups of rare-cutter restriction sites that define CpG islands. The two more centromeric of these islands are associated with transcripts of 3.5 kb and 1.8 kb. The third CpG island maps within <1 kb of the translocation breakpoint in patient AK, as indicated by a genomic rearrangement, and {approximately}100 kb centromeric from another previously mapped translocation breakpoint (patient AnLy). Northern analysis with a probe from this CpG island detected an {approximately}6-kb mRNA in several fetal tissues tested. An extended YAC contig of 1,200 kb with an average of fivefold coverage was constructed. The two most telomeric CpG islands map 350 kb telomeric of the two translocations. Taken together, the results suggest that the CpG island just proximal of the AK translocation breakpoint lies at the 5{prime} end of a candidate gene for EDA. 26 refs., 4 figs., 1 tab.

De novo CpG methylation on an artificial chromosome-like vector maintained for a long-term in mammalian cells.

Science.gov (United States)

Nishioka, Keisuke; Kishida, Tsunao; Masui, Shinji; Mazda, Osam

2016-04-01

To examine whether an autonomously replicating, artificial chromosome-like vector containing a long genomic DNA sequence (namely, Epigenosome-Nanog) undergoes de novo CpG methylation after maintenance in cultured cells for more than a half year. Epigenosome-Nanog efficiently replicated in iPS cells after transfection. In HeLa and C2C12 cells Epigenosome-Nanog was stably maintained for more than eight months. The CpG methylation occurred de novo at the Nanog gene promoter region on the epigenosome in C2C12 cells but the degrees of methylation were much lower than those at the same CpG sites on the chromosomes. Among the four CpG sites at the region, the upstream two CpGs underwent methylation in a correlated manner while methylation at the downstream two CpGs was also correlated to each other, and these correlations were commonly shared between the epigenosome and the chromosome. CpG methylation thus was not solely dependent on the nucleotide sequence at the DNA locus. The epigenosome may become a useful tool to study the mechanisms of epigenetic regulation of a genetic region of interest in mammalian cells.

Phase 1 trial of AMA1-C1/Alhydrogel plus CPG 7909: an asexual blood-stage vaccine for Plasmodium falciparum malaria.

Directory of Open Access Journals (Sweden)

Gregory E D Mullen

2008-08-01

Full Text Available Apical Membrane Antigen 1 (AMA1, a polymorphic merozoite surface protein, is a leading blood-stage malaria vaccine candidate. This is the first reported use in humans of an investigational vaccine, AMA1-C1/Alhydrogel, with the novel adjuvant CPG 7909.A phase 1 trial was conducted at the University of Rochester with 75 malaria-naive volunteers to assess the safety and immunogenicity of the AMA1-C1/Alhydrogel+CPG 7909 malaria vaccine. Participants were sequentially enrolled and randomized within dose escalating cohorts to receive three vaccinations on days 0, 28 and 56 of either 20 microg of AMA1-C1/Alhydrogel+564 microg CPG 7909 (n = 15, 80 microg of AMA1-C1/Alhydrogel (n = 30, or 80 microg of AMA1-C1/Alhydrogel+564 microg CPG 7909 (n = 30.Local and systemic adverse events were significantly more likely to be of higher severity with the addition of CPG 7909. Anti-AMA1 immunoglobulin G (IgG were detected by enzyme-linked immunosorbent assay (ELISA, and the immune sera of volunteers that received 20 microg or 80 microg of AMA1-C1/Alhydrogel+CPG 7909 had up to 14 fold significant increases in anti-AMA1 antibody concentration compared to 80 microg of AMA1-C1/Alhydrogel alone. The addition of CPG 7909 to the AMA1-C1/Alhydrogel vaccine in humans also elicited AMA1 specific immune IgG that significantly and dramatically increased the in vitro growth inhibition of homologous parasites to levels as high as 96% inhibition.The safety profile of the AMA1-C1/Alhydrogel+CPG 7909 malaria vaccine is acceptable, given the significant increase in immunogenicity observed. Further clinical development is ongoing.ClinicalTrials.gov NCT00344539.

Association of the colorectal CpG island methylator phenotype with molecular features, risk factors, and family history.

Science.gov (United States)

Weisenberger, Daniel J; Levine, A Joan; Long, Tiffany I; Buchanan, Daniel D; Walters, Rhiannon; Clendenning, Mark; Rosty, Christophe; Joshi, Amit D; Stern, Mariana C; LeMarchand, Loic; Lindor, Noralane M; Daftary, Darshana; Gallinger, Steven; Selander, Teresa; Bapat, Bharati; Newcomb, Polly A; Campbell, Peter T; Casey, Graham; Ahnen, Dennis J; Baron, John A; Haile, Robert W; Hopper, John L; Young, Joanne P; Laird, Peter W; Siegmund, Kimberly D

2015-03-01

The CpG island methylator phenotype (CIMP) represents a subset of colorectal cancers characterized by widespread aberrant DNA hypermethylation at select CpG islands. The risk factors and environmental exposures contributing to etiologic heterogeneity between CIMP and non-CIMP tumors are not known. We measured the CIMP status of 3,119 primary population-based colorectal cancer tumors from the multinational Colon Cancer Family Registry. Etiologic heterogeneity was assessed by a case-case study comparing risk factor frequency of colorectal cancer cases with CIMP and non-CIMP tumors using logistic regression to estimate the case-case odds ratio (ccOR). We found associations between tumor CIMP status and MSI-H (ccOR = 7.6), BRAF V600E mutation (ccOR = 59.8), proximal tumor site (ccOR = 9; all P CIMP status for both males and females (P = 0.0001 and P = 0.02, respectively), use of multivitamin or calcium supplements did not. Only for female colorectal cancer was CIMP status associated with increased pack-years of smoking (Ptrend CIMP status, and the associations of smoking and obesity with tumor subtype were evident only for females. Differences in the associations of a unique DNA methylation-based subgroup of colorectal cancer with important lifestyle and environmental exposures increase understanding of the molecular pathologic epidemiology of this heavily methylated subset of colorectal cancer. Cancer Epidemiol Biomarkers Prev; 24(3); 512-9. ©2015 AACR. ©2015 American Association for Cancer Research.

A novel CpG island set identifies tissue-specific methylation at developmental gene loci.

Directory of Open Access Journals (Sweden)

Robert Illingworth

2008-01-01

Full Text Available CpG islands (CGIs are dense clusters of CpG sequences that punctuate the CpG-deficient human genome and associate with many gene promoters. As CGIs also differ from bulk chromosomal DNA by their frequent lack of cytosine methylation, we devised a CGI enrichment method based on nonmethylated CpG affinity chromatography. The resulting library was sequenced to define a novel human blood CGI set that includes many that are not detected by current algorithms. Approximately half of CGIs were associated with annotated gene transcription start sites, the remainder being intra- or intergenic. Using an array representing over 17,000 CGIs, we established that 6%-8% of CGIs are methylated in genomic DNA of human blood, brain, muscle, and spleen. Inter- and intragenic CGIs are preferentially susceptible to methylation. CGIs showing tissue-specific methylation were overrepresented at numerous genetic loci that are essential for development, including HOX and PAX family members. The findings enable a comprehensive analysis of the roles played by CGI methylation in normal and diseased human tissues.

Rapid Induction of Protective Immunity Against Biothreat Agents Using CPG-Based Oglionucleotides

National Research Council Canada - National Science Library

Klinman, Dennise

2001-01-01

.... Additional studies examining the ability of these CpG ODN to act as adjuvants when co-administered with vaccines being developed to prevent infection by biowarfare pathogens are also being pursued...

Rapid Induction of Protective Immunity Against Biothreat Agents Using CPG-Based Oglionucleotides

National Research Council Canada - National Science Library

Klinman, Dennise

2001-01-01

This research project examines the ability of synthetic oligonucleotides (ODN) containing immunostimulatory 'CpG motifs' to trigger the innate immune system, thereby improving the host's ability to survive infection by biowarfare agents...

Rapid Induction of Protective Immunity Against Biothreat Agents Using CPG-Based Oligonucleotides

National Research Council Canada - National Science Library

Klinman, Dennis

2003-01-01

This research project examines the ability of synthetic oligonucleotides (ODN) containing immunostimulatory "CpG motifs' to trigger the innate immune system, thereby improving the host's ability to survive infection by biowarfare agents...

Rapid Induction of Protective Immunity Against Biothreat Agens Using CPG-Based Oglionucleotides

National Research Council Canada - National Science Library

Klinman, Dennis

1999-01-01

This research project examines the ability of synthetic oligonucleotides (ODN) containing immunostimulatory 'CpG' motifs to trigger the innate immune system, thereby improving the host's ability to survive infection by biowarfare agents...

CpG promoter methylation of the ALKBH3 alkylation repair gene in breast cancer.

Science.gov (United States)

Stefansson, Olafur Andri; Hermanowicz, Stefan; van der Horst, Jasper; Hilmarsdottir, Holmfridur; Staszczak, Zuzanna; Jonasson, Jon Gunnlaugur; Tryggvadottir, Laufey; Gudjonsson, Thorkell; Sigurdsson, Stefan

2017-07-05

DNA repair of alkylation damage is defective in various cancers. This occurs through somatically acquired inactivation of the MGMT gene in various cancer types, including breast cancers. In addition to MGMT, the two E. coli AlkB homologs ALKBH2 and ALKBH3 have also been linked to direct reversal of alkylation damage. However, it is currently unknown whether ALKBH2 or ALKBH3 are found inactivated in cancer. Methylome datasets (GSE52865, GSE20713, GSE69914), available through Omnibus, were used to determine whether ALKBH2 or ALKBH3 are found inactivated by CpG promoter methylation. TCGA dataset enabled us to then assess the impact of CpG promoter methylation on mRNA expression for both ALKBH2 and ALKBH3. DNA methylation analysis for the ALKBH3 promoter region was carried out by pyrosequencing (PyroMark Q24) in 265 primary breast tumours and 30 proximal normal breast tissue samples along with 8 breast-derived cell lines. ALKBH3 mRNA and protein expression were analysed in cell lines using RT-PCR and Western blotting, respectively. DNA alkylation damage assay was carried out in cell lines based on immunofluorescence and confocal imaging. Data on clinical parameters and survival outcomes in patients were obtained and assessed in relation to ALKBH3 promoter methylation. The ALKBH3 gene, but not ALKBH2, undergoes CpG promoter methylation and transcriptional silencing in breast cancer. We developed a quantitative alkylation DNA damage assay based on immunofluorescence and confocal imaging revealing higher levels of alkylation damage in association with epigenetic inactivation of the ALKBH3 gene (P = 0.029). In our cohort of 265 primary breast cancer, we found 72 cases showing aberrantly high CpG promoter methylation over the ALKBH3 promoter (27%; 72 out of 265). We further show that increasingly higher degree of ALKBH3 promoter methylation is associated with reduced breast-cancer specific survival times in patients. In this analysis, ALKBH3 promoter methylation at >20

CpG oligodeoxynucleotides containing GACGTT motifs enhance the immune responses elicited by a goose parvovirus vaccine in ducks.

Science.gov (United States)

Lee, Jai-Wei; Lin, Yu-Ming; Yen, Ting-Ying; Yang, Wen-Jen; Chu, Chun-Yen

2010-11-23

Recombinant parvovirus VP2 (rVP2) was formulated with different types of adjuvant, including aluminum adjuvant and CpG oligodeoxynucleotides (ODNs), and the immunological responses after vaccination in ducks were examined. In comparison with the control group, production of rVP2-specific antibodies, expression of cytokines in peripheral blood mononuclear cells (PBMC) stimulated by rVP2, and percentage of CD4(+)/CD8(+) cells in PBMC were significantly increased in ducks immunized with rVP2 formulated with CpG ODNs containing 3 copies of GACGTT motif. CpG ODNs with GACGTT motifs might be used to improve the efficacy of vaccines for ducks. Copyright © 2010 Elsevier Ltd. All rights reserved.

Intratracheal synthetic CpG oligodeoxynucleotide causes acute lung injury with systemic inflammatory response

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Hasegawa Naoki

2009-09-01

Full Text Available Abstract Bacterial genome is characterized by frequent unmethylated cytosine-phosphate-guanine (CpG motifs. Deleterious effects can occur when synthetic oligodeoxynucleotides (ODN with unmethylated CpG dinucleotides (CpG-ODN are administered in a systemic fashion. We aimed to evaluate the effect of intratracheal CpG-ODN on lung inflammation and systemic inflammatory response. C57BL/6J mice received intratracheal administration of CpG-ODN (0.01, 0.1, 1.0, 10, or 100 μM or control ODN without CpG motif. Bronchoalveolar lavage (BAL fluid was obtained 3 or 6 h or 1, 2, 7, or 14 days after the instillation and subjected to a differential cell count and cytokine measurement. Lung permeability was evaluated as the BAL fluid-to-plasma ratio of the concentration of human serum albumin that was injected 1 h before euthanasia. Nuclear factor (NF-κB DNA binding activity was also evaluated in lung homogenates. Intratracheal administration of 10 μM or higher concentration of CpG-ODN induced significant inflammatory cell accumulation into the airspace. The peak accumulation of neutrophils and lymphocytes occurred 1 and 2 days after the CpG-ODN administration, respectively. Lung permeability was increased 1 day after the 10 μM CpG-ODN challenge. CpG-ODN also induced nuclear translocation of NF-κB and upregulation of various inflammatory cytokines in BAL fluid and plasma. Histopathology of the lungs and liver revealed acute lung injury and liver damage with necrosis, respectively. Control ODN without CpG motif did not induce any inflammatory change. Since intratracheal CpG-ODN induced acute lung injury as well as systemic inflammatory response, therapeutic strategies to neutralize bacterial DNA that is released after administration of bactericidal agents should be considered.

Immortalization of T-Cells Is Accompanied by Gradual Changes in CpG Methylation Resulting in a Profile Resembling a Subset of T-Cell Leukemias

Directory of Open Access Journals (Sweden)

Sofie Degerman

2014-07-01

Full Text Available We have previously described gene expression changes during spontaneous immortalization of T-cells, thereby identifying cellular processes important for cell growth crisis escape and unlimited proliferation. Here, we analyze the same model to investigate the role of genome-wide methylation in the immortalization process at different time points pre-crisis and post-crisis using high-resolution arrays. We show that over time in culture there is an overall accumulation of methylation alterations, with preferential increased methylation close to transcription start sites (TSSs, islands, and shore regions. Methylation and gene expression alterations did not correlate for the majority of genes, but for the fraction that correlated, gain of methylation close to TSS was associated with decreased gene expression. Interestingly, the pattern of CpG site methylation observed in immortal T-cell cultures was similar to clinical T-cell acute lymphoblastic leukemia (T-ALL samples classified as CpG island methylator phenotype positive. These sites were highly overrepresented by polycomb target genes and involved in developmental, cell adhesion, and cell signaling processes. The presence of non-random methylation events in in vitro immortalized T-cell cultures and diagnostic T-ALL samples indicates altered methylation of CpG sites with a possible role in malignant hematopoiesis.

CpG methylation controls reactivation of HIV from latency

Czech Academy of Sciences Publication Activity Database

Blažková, Jana; Trejbalová, Kateřina; Gondois-Rey, F.; Halfon, P.; Philibert, P.; Guiguen, A.; Verdin, E.; Olive, D.; Van Lint, C.; Hejnar, Jiří; Hirsch, I.

2009-01-01

Roč. 5, č. 8 (2009), e1000554-e1000554 E-ISSN 1553-7374 R&D Projects: GA ČR GA204/05/0939; GA ČR GP204/08/P616 Institutional research plan: CEZ:AV0Z50520514 Keywords : HIV-1 * proviral latency * CpG methylation * histone modifications * HAART * epigenetics Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 8.978, year: 2009

Optimization of polynomials in non-commuting variables

CERN Document Server

Burgdorf, Sabine; Povh, Janez

2016-01-01

This book presents recent results on positivity and optimization of polynomials in non-commuting variables. Researchers in non-commutative algebraic geometry, control theory, system engineering, optimization, quantum physics and information science will find the unified notation and mixture of algebraic geometry and mathematical programming useful. Theoretical results are matched with algorithmic considerations; several examples and information on how to use NCSOStools open source package to obtain the results provided. Results are presented on detecting the eigenvalue and trace positivity of polynomials in non-commuting variables using Newton chip method and Newton cyclic chip method, relaxations for constrained and unconstrained optimization problems, semidefinite programming formulations of the relaxations and finite convergence of the hierarchies of these relaxations, and the practical efficiency of algorithms.

Deletions of a differentially methylated CpG island at SNRPN define a putative imprinting control region

Energy Technology Data Exchange (ETDEWEB)

Sutcliffe, J.S.,; Nakao, M.; Beaudet, A.L. [Baylor College of Medicine, Houston, TX (United States)] [and others

1994-09-01

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are associated with paternal and maternal deficiencies, respectively, of gene expression within human chromosome 15q11-q13, and are caused by deletion, uniparental disomy, or other mutations. Four transcripts designated PAR-5, PAR-7, PAR-1 and PAR-4 were isolated and localized to a region within 300 kb telomeric to the gene encoding small nuclear ribonucleoprotein-associated polypeptide N (SNRPN). Analysis of the transcripts in cultured fibroblasts and lymphoblasts from deletion patients demonstrated that SNRPN, PAR-5 and PAR-1 are expressed exclusively from the paternal chromosome, defining an imprinted domain that spans at least 200 kb. All three imprinted transcripts were absent in cells from three PWS patients (one pair of sibs and one sporadic case) with small deletions that involve a differentially methylated CpG island containing a previously undescribed 5{prime} untranslated exon ({alpha}) of SNRPN. Methylation of the CpG island is specific for the maternal chromosome consistent with paternal expression of the imprinted domain. One deletion, which is benign when maternally transmitted, extends upstream <30 kb from the CpG island, and is associated with altered methylation centromeric to SNRPN, and loss of transcription telomeric to SNRPN, implying the presence of an imprinting control region around the CpG island containing exon {alpha}.

Non-Communicable Disease Clinical Practice Guidelines in Brazil: A Systematic Assessment of Methodological Quality and Transparency.

Directory of Open Access Journals (Sweden)

Caroline de Godoi Rezende Costa Molino

Full Text Available Annually, non-communicable diseases (NCDs kill 38 million people worldwide, with low and middle-income countries accounting for three-quarters of these deaths. High-quality clinical practice guidelines (CPGs are fundamental to improving NCD management. The present study evaluated the methodological rigor and transparency of Brazilian CPGs that recommend pharmacological treatment for the most prevalent NCDs.We conducted a systematic search for CPGs of the following NCDs: asthma, atrial fibrillation, benign prostatic hyperplasia, chronic obstructive pulmonary disease, congestive heart failure, coronary artery disease and/or stable angina, dementia, depression, diabetes, gastroesophageal reflux disease, hypercholesterolemia, hypertension, osteoarthritis, and osteoporosis. CPGs comprising pharmacological treatment recommendations were included. No language or year restrictions were applied. CPGs were excluded if they were merely for local use and referred to NCDs not listed above. CPG quality was independently assessed by two reviewers using the Appraisal of Guidelines Research and Evaluation instrument, version II (AGREE II."Scope and purpose" and "clarity and presentation" domains received the highest scores. Sixteen of 26 CPGs were classified as low quality, and none were classified as high overall quality. No CPG was recommended without modification (77% were not recommended at all. After 2009, 2 domain scores ("rigor of development" and "clarity and presentation" increased (61% and 73%, respectively. However, "rigor of development" was still rated < 30%.Brazilian healthcare professionals should be concerned with CPG quality for the treatment of selected NCDs. Features that undermined AGREE II scores included the lack of a multidisciplinary team for the development group, no consideration of patients' preferences, insufficient information regarding literature searches, lack of selection criteria, formulating recommendations, authors' conflict of

Systematic CpT (ApG) Depletion and CpG Excess Are Unique Genomic Signatures of Large DNA Viruses Infecting Invertebrates

Science.gov (United States)

Upadhyay, Mohita; Sharma, Neha; Vivekanandan, Perumal

2014-01-01

Differences in the relative abundance of dinucleotides, if any may provide important clues on host-driven evolution of viruses. We studied dinucleotide frequencies of large DNA viruses infecting vertebrates (n = 105; viruses infecting mammals = 99; viruses infecting aves = 6; viruses infecting reptiles = 1) and invertebrates (n = 88; viruses infecting insects = 84; viruses infecting crustaceans = 4). We have identified systematic depletion of CpT(ApG) dinucleotides and over-representation of CpG dinucleotides as the unique genomic signature of large DNA viruses infecting invertebrates. Detailed investigation of this unique genomic signature suggests the existence of invertebrate host-induced pressures specifically targeting CpT(ApG) and CpG dinucleotides. The depletion of CpT dinucleotides among large DNA viruses infecting invertebrates is at least in part, explained by non-canonical DNA methylation by the infected host. Our findings highlight the role of invertebrate host-related factors in shaping virus evolution and they also provide the necessary framework for future studies on evolution, epigenetics and molecular biology of viruses infecting this group of hosts. PMID:25369195

Phosphoinositide 3-kinaseγ controls the intracellular localization of CpG to limit DNA-PKcs-dependent IL-10 production in macrophages.

Directory of Open Access Journals (Sweden)

Kaoru Hazeki

Full Text Available Synthetic oligodeoxynucleotides containing unmethylated CpG motifs (CpG stimulate innate immune responses. Phosphoinositide 3-kinase (PI3K has been implicated in CpG-induced immune activation; however, its precise role has not yet been clarified. CpG-induced production of IL-10 was dramatically increased in macrophages deficient in PI3Kγ (p110γ(-/-. By contrast, LPS-induced production of IL-10 was unchanged in the cells. CpG-induced, but not LPS-induced, IL-10 production was almost completely abolished in SCID mice having mutations in DNA-dependent protein kinase catalytic subunit (DNA-PKcs. Furthermore, wortmannin, an inhibitor of DNA-PKcs, completely inhibited CpG-induced IL-10 production, both in wild type and p110γ(-/- cells. Microscopic analyses revealed that CpG preferentially localized with DNA-PKcs in p110γ(-/- cells than in wild type cells. In addition, CpG was preferentially co-localized with the acidic lysosomal marker, LysoTracker, in p110γ(-/- cells, and with an early endosome marker, EEA1, in wild type cells. Over-expression of p110γ in Cos7 cells resulted in decreased acidification of CpG containing endosome. A similar effect was reproduced using kinase-dead mutants, but not with a ras-binding site mutant, of p110γ. Thus, it is likely that p110γ, in a manner independent of its kinase activity, inhibits the acidification of CpG-containing endosomes. It is considered that increased acidification of CpG-containing endosomes in p110γ(-/- cells enforces endosomal escape of CpG, which results in increased association of CpG with DNA-PKcs to up-regulate IL-10 production in macrophages.

CpG Methylation Analysis—Current Status of Clinical Assays and Potential Applications in Molecular Diagnostics

Science.gov (United States)

Sepulveda, Antonia R.; Jones, Dan; Ogino, Shuji; Samowitz, Wade; Gulley, Margaret L.; Edwards, Robin; Levenson, Victor; Pratt, Victoria M.; Yang, Bin; Nafa, Khedoudja; Yan, Liying; Vitazka, Patrick

2009-01-01

Methylation of CpG islands in gene promoter regions is a major molecular mechanism of gene silencing and underlies both cancer development and progression. In molecular oncology, testing for the CpG methylation of tissue DNA has emerged as a clinically useful tool for tumor detection, outcome prediction, and treatment selection, as well as for assessing the efficacy of treatment with the use of demethylating agents and monitoring for tumor recurrence. In addition, because CpG methylation occurs early in pre-neoplastic tissues, methylation tests may be useful as markers of cancer risk in patients with either infectious or inflammatory conditions. The Methylation Working Group of the Clinical Practice Committee of the Association of Molecular Pathology has reviewed the current state of clinical testing in this area. We report here our summary of both the advantages and disadvantages of various methods, as well as the needs for standardization and reporting. We then conclude by summarizing the most promising areas for future clinical testing in cancer molecular diagnostics. PMID:19541921

Phase 1 testing of detoxified LPS/group B meningococcal outer membrane protein vaccine with and without synthetic CPG 7909 adjuvant for the prevention and treatment of sepsis.

Science.gov (United States)

Cross, Alan S; Greenberg, Nancy; Billington, Melissa; Zhang, Lei; DeFilippi, Christopher; May, Ryan C; Bajwa, Kanwaldeep K

2015-11-27

Gram-negative bacteria (GNB) are a leading cause of nosocomial infection and sepsis. Increasing multi-antibiotic resistance has left clinicians with fewer therapeutic options. Antibodies to GNB lipopolysaccharide (LPS, or endotoxin) have reduced morbidity and mortality as a result of infection and are not subject to the resistance mechanisms deployed by bacteria against antibiotics. In this phase 1 study, we administered a vaccine that elicits antibodies against a highly conserved portion of LPS with and without a CpG oligodeoxynucleotide (ODN) TLR9 agonist as adjuvant. A vaccine composed of the detoxified LPS (dLPS) from E. coli O111:B4 (J5 mutant) non-covalently complexed to group B meningococcal outer membrane protein (OMP). Twenty healthy adult subjects received three doses at 0, 29 and 59 days of antigen (10 μg dLPS) with or without CPG 7909 (250 or 500 μg). Subjects were evaluated for local and systemic adverse effects and laboratory findings. Anti-J5 LPS IgG and IgM antibody levels were measured by electrochemiluminesence. Due to premature study termination, not all subjects received all three doses. All vaccine formulations were well-tolerated with no local or systemic events of greater than moderate severity. The vaccine alone group achieved a ≥ 4-fold "responder" response in IgG and IgM antibody in only one of 6 subjects. In contrast, the vaccine plus CPG 7909 groups appeared to have earlier and more sustained (to 180 days) responses, greater mean-fold increases, and a higher proportion of "responders" achieving ≥ 4-fold increases over baseline. Although the study was halted before all enrolled subjects received all three doses, the J5dLPS/OMP vaccine, with or without CpG adjuvant, was safe and well-tolerated. The inclusion of CpG increased the number of subjects with a ≥ 4-fold antibody response, evident even after the second of three planned doses. A vaccine comprising J5dLPS/OMP antigen with CpG adjuvant merits further investigation. Clinical

Long-range autocorrelations of CpG islands in the human genome.

Directory of Open Access Journals (Sweden)

Benjamin Koester

Full Text Available In this paper, we use a statistical estimator developed in astrophysics to study the distribution and organization of features of the human genome. Using the human reference sequence we quantify the global distribution of CpG islands (CGI in each chromosome and demonstrate that the organization of the CGI across a chromosome is non-random, exhibits surprisingly long range correlations (10 Mb and varies significantly among chromosomes. These correlations of CGI summarize functional properties of the genome that are not captured when considering variation in any particular separate (and local feature. The demonstration of the proposed methods to quantify the organization of CGI in the human genome forms the basis of future studies. The most illuminating of these will assess the potential impact on phenotypic variation of inter-individual variation in the organization of the functional features of the genome within and among chromosomes, and among individuals for particular chromosomes.

Immortalization of T-cells is accompanied by gradual changes in CpG methylation resulting in a profile resembling a subset of T-cell leukemias.

Science.gov (United States)

Degerman, Sofie; Landfors, Mattias; Siwicki, Jan Konrad; Revie, John; Borssén, Magnus; Evelönn, Emma; Forestier, Erik; Chrzanowska, Krystyna H; Rydén, Patrik; Keith, W Nicol; Roos, Göran

2014-07-01

We have previously described gene expression changes during spontaneous immortalization of T-cells, thereby identifying cellular processes important for cell growth crisis escape and unlimited proliferation. Here, we analyze the same model to investigate the role of genome-wide methylation in the immortalization process at different time points pre-crisis and post-crisis using high-resolution arrays. We show that over time in culture there is an overall accumulation of methylation alterations, with preferential increased methylation close to transcription start sites (TSSs), islands, and shore regions. Methylation and gene expression alterations did not correlate for the majority of genes, but for the fraction that correlated, gain of methylation close to TSS was associated with decreased gene expression. Interestingly, the pattern of CpG site methylation observed in immortal T-cell cultures was similar to clinical T-cell acute lymphoblastic leukemia (T-ALL) samples classified as CpG island methylator phenotype positive. These sites were highly overrepresented by polycomb target genes and involved in developmental, cell adhesion, and cell signaling processes. The presence of non-random methylation events in in vitro immortalized T-cell cultures and diagnostic T-ALL samples indicates altered methylation of CpG sites with a possible role in malignant hematopoiesis. Copyright © 2014 Neoplasia Press, Inc. Published by Elsevier Inc. All rights reserved.

Restoration of CpG Methylation in The Egf Promoter Region during Rat Liver Regeneration

Science.gov (United States)

Deming, Li; Ziwei, Li; Xueqiang, Guo; Cunshuan, Xu

2015-01-01

Epidermal growth factor (EGF) is an important factor for healing after tissue damage in diverse experimental models. It plays an important role in liver regeneration (LR). The objective of this experiment is to investigate the methylation variation of 10 CpG sites in the Egf promoter region and their relevance to Egf expression during rat liver regenera- tion. As a follow up of our previous study, rat liver tissue was collected after rat 2/3 partial hepatectomy (PH) during the re-organization phase (from days 14 to days 28). Liver DNA was extracted and modified by sodium bisulfate. The methylation status of 10 CpG sites in Egf promoter region was determined using bisulfite sequencing polymerase chain reaction (PCR), as BSP method. The results showed that 3 (sites 3, 4 and 9) out of 10 CpG sites have strikingly methylation changes during the re-organization phase compared to the regeneration phase (from 2 hours to 168 hours, P=0.002, 0.048 and 0.018, respectively). Our results showed that methylation modification of CpGs in the Egf promoter region could be restored to the status before PH operation and changes of methylation didn’t affect Egf mRNA expression during the re-organization phase. PMID:26464832

Continuous variable entanglement distillation of non-Gaussian states

DEFF Research Database (Denmark)

Lassen, Mikael Østergaard; Dong, Ruifang; Heersink, Joel

2009-01-01

We experimentally demonstrate distillation of continuous variable entangled light that has undergone non-Gaussian attenuation loss. The continuous variable entanglement is generated with optical fibers and sent through a lossy channel, where the transmission is varying in time. By employing simple...

Effects of CPG ODN on biological behavior of PANC-1 and expression of TLR9 in pancreatic cancer.

Science.gov (United States)

Wu, Han-Qing; Wang, Bo; Zhu, Shi-Kai; Tian, Yuan; Zhang, Jing-Hui; Wu, He-Shui

2011-02-28

To determine the expression of toll-like receptor 9 (TLR9) in pancreatic tumor and the effects of cytosine phosphate-guanosine oligodeoxynucleotides 2216 (CPG ODN2216) on biological behavior of pancreatic carcinoma cell line PANC-1 and explore their clinical significance. The immunohistochemistry and Western blot were used to determine the expression of TLR9 protein in pancreatic cancer tissues, and immunofluorescence staining was performed to detect the TLR9 protein expression in pancreatic carcinoma cell line PANC-1. To assess the effects of CPG ODN2216 on the invasive property of Panc-1 cells, in vitro cell adhesion, wound-healing scrape, and invasion and cell colony formation were evaluated. TLR9 was highly expressed in pancreatic cancer tissues and PANC-1 cells. The percentage of positive cells expressing TLR9 protein in human pancreatic tissues, paracancerous tissues and normal tissues were 73.3%, 33.3% and 20.0%, respectively, and the protein expression level of TLR9 was gradually descending (P PANC-1 cells in CPG ODN 2216 treatment group were significantly lower than in the control group (P PANC-1 cells in treatment group was significantly decreased and CPG ODN2216 had an inhibitive effect in the growth of Panc-1 cells in a dose and time-dependent manner (P Panc-1 cells.

FPGA implementation of a configurable neuromorphic CPG-based locomotion controller.

Science.gov (United States)

Barron-Zambrano, Jose Hugo; Torres-Huitzil, Cesar

2013-09-01

Neuromorphic engineering is a discipline devoted to the design and development of computational hardware that mimics the characteristics and capabilities of neuro-biological systems. In recent years, neuromorphic hardware systems have been implemented using a hybrid approach incorporating digital hardware so as to provide flexibility and scalability at the cost of power efficiency and some biological realism. This paper proposes an FPGA-based neuromorphic-like embedded system on a chip to generate locomotion patterns of periodic rhythmic movements inspired by Central Pattern Generators (CPGs). The proposed implementation follows a top-down approach where modularity and hierarchy are two desirable features. The locomotion controller is based on CPG models to produce rhythmic locomotion patterns or gaits for legged robots such as quadrupeds and hexapods. The architecture is configurable and scalable for robots with either different morphologies or different degrees of freedom (DOFs). Experiments performed on a real robot are presented and discussed. The obtained results demonstrate that the CPG-based controller provides the necessary flexibility to generate different rhythmic patterns at run-time suitable for adaptable locomotion. Copyright © 2013 Elsevier Ltd. All rights reserved.

Improvement of the Immunogenicity of Porcine Circovirus Type 2 DNA Vaccine by Recombinant ORF2 Gene and CpG Motifs.

Science.gov (United States)

Li, Jun; Shi, Jian-Li; Wu, Xiao-Yan; Fu, Fang; Yu, Jiang; Yuan, Xiao-Yuan; Peng, Zhe; Cong, Xiao-Yan; Xu, Shao-Jian; Sun, Wen-Bo; Cheng, Kai-Hui; Du, Yi-Jun; Wu, Jia-Qiang; Wang, Jin-Bao; Huang, Bao-Hua

2015-06-01

Nowadays, adjuvant is still important for boosting immunity and improving resistance in animals. In order to boost the immunity of porcine circovirus type 2 (PCV2) DNA vaccine, CpG motifs were inserted. In this study, the dose-effect was studied, and the immunity of PCV2 DNA vaccines by recombinant open reading frame 2 (ORF2) gene and CpG motifs was evaluated. Three-week-old Changbai piglets were inoculated intramuscularly with 200 μg, 400 μg, and 800 μg DNA vaccines containing 14 and 18 CpG motifs, respectively. Average gain and rectum temperature were recorded everyday during the experiments. Blood was collected from the piglets after vaccination to detect the changes of specific antibodies, interleukin-2, and immune cells every week. Tissues were collected for histopathology and polymerase chain reaction. The results indicated that compared to those of the control piglets, all concentrations of two DNA vaccines could induce PCV2-specific antibodies. A cellular immunity test showed that PCV2-specific lymphocytes proliferated the number of TH, TC, and CD3+ positive T-cells raised in the blood of DNA vaccine immune groups. There was no distinct pathological damage and viremia occurring in pigs that were inoculated with DNA vaccines, but there was some minor pathological damage in the control group. The results demonstrated that CpG motifs as an adjuvant could boost the humoral and cellular immunity of pigs to PCV2, especially in terms of cellular immunity. Comparing two DNA vaccines that were constructed, the one containing 18 CpG motifs was more effective. This is the first report that CpG motifs as an adjuvant insert to the PCV2 DNA vaccine could boost immunity.

Newly identified CpG ODNs, M5-30 and M6-395, stimulate mouse immune cells to secrete TNF-alpha and enhance Th1-mediated immunity.

Science.gov (United States)

Choi, Sun-Shim; Chung, Eunkyung; Jung, Yu-Jin

2010-08-01

Bacterial CpG motifs are known to induce both innate and adaptive immunity in infected hosts via toll-like receptor 9 (TLR9). Because small oligonucleotides (ODNs) mimicking bacterial CpG motifs are easily synthesized, they have found use as immunomodulatory agents in a number of disease models. We have developed a novel bioinformatics approach to identify effective CpG ODN sequences and evaluate their function as TLR9 ligands in a murine system. Among the CpG ODNs we identified, M5-30 and M6-395 showed significant ability to stimulate TNF-alpha and IFN-gamma production in a mouse macrophage cell line and mouse splenocytes, respectively. We also found that these CpG ODNs activated cells through the canonical NF-kappa B signaling pathway. Moreover, both CpG ODNs were able to induce Th1-mediated immunity in Mycobacterium tuberculosis (Mtb)-infected mice. Our results demonstrate that M5-30 and M6-395 function as TLR9-specific ligands, making them useful in the study of TLR9 functionality and signaling in mice.

Genome-wide methylation analysis identifies differentially methylated CpG loci associated with severe obesity in childhood.

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Huang, R C; Garratt, E S; Pan, H; Wu, Y; Davis, E A; Barton, S J; Burdge, G C; Godfrey, K M; Holbrook, J D; Lillycrop, K A

2015-01-01

Childhood obesity is a major public health issue. Here we investigated whether differential DNA methylation was associated with childhood obesity. We studied DNA methylation profiles in whole blood from 78 obese children (mean BMI Z-score: 2.6) and 71 age- and sex-matched controls (mean BMI Z-score: 0.1). DNA samples from obese and control groups were pooled and analyzed using the Infinium HumanMethylation450 BeadChip array. Comparison of the methylation profiles between obese and control subjects revealed 129 differentially methylated CpG (DMCpG) loci associated with 80 unique genes that had a greater than 10% difference in methylation (P-value obesity were validated using sodium bisulfite pyrosequencing across loci within the FYN, PIWIL4, and TAOK3 genes in individual subjects. Three CpG loci within FYN were hypermethylated in obese individuals (all P obesity was associated with lower methylation of CpG loci within PIWIL4 (P = 0.003) and TAOK3 (P = 0.001). After building logistic regression models, we determined that a 1% increase in methylation in TAOK3, multiplicatively decreased the odds of being obese by 0.91 (95% CI: 0.86 - 0.97), and an increase of 1% methylation in FYN CpG3, multiplicatively increased the odds of being obese by 1.03 (95% CI: 0.99 - 1.07). In conclusion, these findings provide evidence that childhood obesity is associated with specific DNA methylation changes in whole blood, which may have utility as biomarkers of obesity risk.

AtMBD6, a methyl CpG binding domain protein, maintains gene ...

Indian Academy of Sciences (India)

DNA methylation, mediated by double-stranded RNA, is a conserved epigenetic phenomenon that protects a genome fromtransposons, silences unwanted genes and has a paramount function in plant or animal development. Methyl CpG bindingdomain proteins are members of a class of proteins that bind tomethylated ...

AtMBD6, a methyl CpG binding domain protein, maintains gene ...

Indian Academy of Sciences (India)

2017-01-13

Jan 13, 2017 ... 13 methyl CpG binding domain (MBD) proteins, but the molecular/biological functions of most of these ... AtMBD5, AtMBD6 and AtMBD7 are more similar to those .... prey were able to grow on -AHLW (-Ade, -His, -Leu, -Trp).

Deletion and aberrant CpG island methylation of Caspase 8 gene in medulloblastoma.

Science.gov (United States)

Gonzalez-Gomez, Pilar; Bello, M Josefa; Inda, M Mar; Alonso, M Eva; Arjona, Dolores; Amiñoso, Cinthia; Lopez-Marin, Isabel; de Campos, Jose M; Sarasa, Jose L; Castresana, Javier S; Rey, Juan A

2004-09-01

Aberrant methylation of promoter CpG islands in human genes is an alternative genetic inactivation mechanism that contributes to the development of human tumors. Nevertheless, few studies have analyzed methylation in medulloblastomas. We determined the frequency of aberrant CpG island methylation for Caspase 8 (CASP8) in a group of 24 medulloblastomas arising in 8 adult and 16 pediatric patients. Complete methylation of CASP8 was found in 15 tumors (62%) and one case displayed hemimethylation. Three samples amplified neither of the two primer sets for methylated or unmethylated alleles, suggesting that genomic deletion occurred in the 5' flanking region of CASP8. Our findings suggest that methylation commonly contributes to CASP8 silencing in medulloblastomas and that homozygous deletion or severe sequence changes involving the promoter region may be another mechanism leading to CASP8 inactivation in this neoplasm.

Non-native Listeners’ Recognition of High-Variability Speech Using PRESTO

Science.gov (United States)

Tamati, Terrin N.; Pisoni, David B.

2015-01-01

Background Natural variability in speech is a significant challenge to robust successful spoken word recognition. In everyday listening environments, listeners must quickly adapt and adjust to multiple sources of variability in both the signal and listening environments. High-variability speech may be particularly difficult to understand for non-native listeners, who have less experience with the second language (L2) phonological system and less detailed knowledge of sociolinguistic variation of the L2. Purpose The purpose of this study was to investigate the effects of high-variability sentences on non-native speech recognition and to explore the underlying sources of individual differences in speech recognition abilities of non-native listeners. Research Design Participants completed two sentence recognition tasks involving high-variability and low-variability sentences. They also completed a battery of behavioral tasks and self-report questionnaires designed to assess their indexical processing skills, vocabulary knowledge, and several core neurocognitive abilities. Study Sample Native speakers of Mandarin (n = 25) living in the United States recruited from the Indiana University community participated in the current study. A native comparison group consisted of scores obtained from native speakers of English (n = 21) in the Indiana University community taken from an earlier study. Data Collection and Analysis Speech recognition in high-variability listening conditions was assessed with a sentence recognition task using sentences from PRESTO (Perceptually Robust English Sentence Test Open-Set) mixed in 6-talker multitalker babble. Speech recognition in low-variability listening conditions was assessed using sentences from HINT (Hearing In Noise Test) mixed in 6-talker multitalker babble. Indexical processing skills were measured using a talker discrimination task, a gender discrimination task, and a forced-choice regional dialect categorization task. Vocabulary

Clarifying the use of aggregated exposures in multilevel models: self-included vs. self-excluded measures.

Directory of Open Access Journals (Sweden)

Etsuji Suzuki

Full Text Available Multilevel analyses are ideally suited to assess the effects of ecological (higher level and individual (lower level exposure variables simultaneously. In applying such analyses to measures of ecologies in epidemiological studies, individual variables are usually aggregated into the higher level unit. Typically, the aggregated measure includes responses of every individual belonging to that group (i.e. it constitutes a self-included measure. More recently, researchers have developed an aggregate measure which excludes the response of the individual to whom the aggregate measure is linked (i.e. a self-excluded measure. In this study, we clarify the substantive and technical properties of these two measures when they are used as exposures in multilevel models.Although the differences between the two aggregated measures are mathematically subtle, distinguishing between them is important in terms of the specific scientific questions to be addressed. We then show how these measures can be used in two distinct types of multilevel models-self-included model and self-excluded model-and interpret the parameters in each model by imposing hypothetical interventions. The concept is tested on empirical data of workplace social capital and employees' systolic blood pressure.Researchers assume group-level interventions when using a self-included model, and individual-level interventions when using a self-excluded model. Analytical re-parameterizations of these two models highlight their differences in parameter interpretation. Cluster-mean centered self-included models enable researchers to decompose the collective effect into its within- and between-group components. The benefit of cluster-mean centering procedure is further discussed in terms of hypothetical interventions.When investigating the potential roles of aggregated variables, researchers should carefully explore which type of model-self-included or self-excluded-is suitable for a given situation

Dengue-1 envelope protein domain III along with PELC and CpG oligodeoxynucleotides synergistically enhances immune responses.

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Chen-Yi Chiang

Full Text Available The major weaknesses of subunit vaccines are their low immunogenicity and poor efficacy. Adjuvants can help to overcome some of these inherent defects with subunit vaccines. Here, we evaluated the efficacy of the newly developed water-in-oil-in-water multiphase emulsion system, termed PELC, in potentiating the protective capacity of dengue-1 envelope protein domain III. Unlike aluminum phosphate, dengue-1 envelope protein domain III formulated with PELC plus CpG oligodeoxynucleotides induced neutralizing antibodies against dengue-1 virus and increased the splenocyte secretion of IFN-γ after in vitro re-stimulation. The induced antibodies contained both the IgG1 and IgG2a subclasses. A rapid anamnestic neutralizing antibody response against a live dengue virus challenge was elicited at week 26 after the first immunization. These results demonstrate that PELC plus CpG oligodeoxynucleotides broaden the dengue-1 envelope protein domain III-specific immune responses. PELC plus CpG oligodeoxynucleotides is a promising adjuvant for recombinant protein based vaccination against dengue virus.

Methylation status of individual CpG sites within Alu elements in the human genome and Alu hypomethylation in gastric carcinomas

International Nuclear Information System (INIS)

Xiang, Shengyan; Liu, Zhaojun; Zhang, Baozhen; Zhou, Jing; Zhu, Bu-Dong; Ji, Jiafu; Deng, Dajun

2010-01-01

Alu methylation is correlated with the overall level of DNA methylation and recombination activity of the genome. However, the maintenance and methylation status of each CpG site within Alu elements (Alu) and its methylation status have not well characterized. This information is useful for understanding natural status of Alu in the genome and helpful for developing an optimal assay to quantify Alu hypomethylation. Bisulfite clone sequencing was carried out in 14 human gastric samples initially. A Cac8I COBRA-DHPLC assay was developed to detect methylated-Alu proportion in cell lines and 48 paired gastric carcinomas and 55 gastritis samples. DHPLC data were statistically interpreted using SPSS version 16.0. From the results of 427 Alu bisulfite clone sequences, we found that only 27.2% of CpG sites within Alu elements were preserved (4.6 of 17 analyzed CpGs, A ~ Q) and that 86.6% of remaining-CpGs were methylated. Deamination was the main reason for low preservation of methylation targets. A high correlation coefficient of methylation was observed between Alu clones and CpG site J (0.963), A (0.950), H (0.946), D (0.945). Comethylation of the sites H and J were used as an indicator of the proportion of methylated-Alu in a Cac8I COBRA-DHPLC assay. Validation studies showed that hypermethylation or hypomethylation of Alu elements in human cell lines could be detected sensitively by the assay after treatment with 5-aza-dC and M.SssI, respectively. The proportion of methylated-Alu copies in gastric carcinomas (3.01%) was significantly lower than that in the corresponding normal samples (3.19%) and gastritis biopsies (3.23%). Most Alu CpG sites are deaminated in the genome. 27% of Alu CpG sites represented in our amplification products. 87% of the remaining CpG sites are methylated. Alu hypomethylation in primary gastric carcinomas could be detected with the Cac8I COBRA-DHPLC assay quantitatively

DELETION AND 5'CPG ISLAND METHYLATION OF p15 GENE IN BRAIN GLIOMA

Institute of Scientific and Technical Information of China (English)

无

2000-01-01

Objective: To investigate the abnormality of p15 gene in brain glioma and the correlation of it with occurrence or malignant progression of brain glioma. Methods: Deletion and 5'CPG island methylation of p15 gene were detected by the methods of PCR and PCR-based methylation in 56 cases of brain glioma. Results: Out of 43 cases of high grade glioma, 14 cases were found to have homozygous deletion of p15E1, while none of the 13 cases of low grade glioma was found to have deletion of p15E1 (P<0.05). Methylation of 5'CPG Island of p15 gene was found only in four cases of glioma. Conclusion: Abnormality of p15 gene may involved in the occurrence and malignant progression of brain glioma. Homozygous deletion of gene is the major mechanism of inactivation for p15 gene in brain glioma.

DMPD: Signal transduction pathways mediated by the interaction of CpG DNA withToll-like receptor 9. [Dynamic Macrophage Pathway CSML Database

Lifescience Database Archive (English)

Full Text Available 14751759 Signal transduction pathways mediated by the interaction of CpG DNA withTo...;16(1):17-22. (.png) (.svg) (.html) (.csml) Show Signal transduction pathways mediated by the interaction of... CpG DNA withToll-like receptor 9. PubmedID 14751759 Title Signal transduction pathways media

Completion of hepatitis C virus replication cycle in heterokaryons excludes dominant restrictions in human non-liver and mouse liver cell lines.

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Anne Frentzen

2011-04-01

Full Text Available Hepatitis C virus (HCV is hepatotropic and only infects humans and chimpanzees. Consequently, an immunocompetent small animal model is lacking. The restricted tropism of HCV likely reflects specific host factor requirements. We investigated if dominant restriction factors expressed in non-liver or non-human cell lines inhibit HCV propagation thus rendering these cells non-permissive. To this end we explored if HCV completes its replication cycle in heterokaryons between human liver cell lines and non-permissive cell lines from human non-liver or mouse liver origin. Despite functional viral pattern recognition pathways and responsiveness to interferon, virus production was observed in all fused cells and was only ablated when cells were treated with exogenous interferon. These results exclude that constitutive or virus-induced expression of dominant restriction factors prevents propagation of HCV in these cell types, which has important implications for HCV tissue and species tropism. In turn, these data strongly advocate transgenic approaches of crucial human HCV cofactors to establish an immunocompetent small animal model.

Partial summations of stationary sequences of non-Gaussian random variables

DEFF Research Database (Denmark)

Mohr, Gunnar; Ditlevsen, Ove Dalager

1996-01-01

The distribution of the sum of a finite number of identically distributed random variables is in many cases easily determined given that the variables are independent. The moments of any order of the sum can always be expressed by the moments of the single term without computational problems...... of convergence of the distribution of a sum (or an integral) of mutually dependent random variables to the Gaussian distribution. The paper is closely related to the work in Ditlevsen el al. [Ditlevsen, O., Mohr, G. & Hoffmeyer, P. Integration of non-Gaussian fields. Prob. Engng Mech 11 (1996) 15-23](2)....... lognormal variables or polynomials of standard Gaussian variables. The dependency structure is induced by specifying the autocorrelation structure of the sequence of standard Gaussian variables. Particularly useful polynomials are the Winterstein approximations that distributionally fit with non...

Continuous-variable quantum teleportation with non-Gaussian resources

International Nuclear Information System (INIS)

Dell'Anno, F.; De Siena, S.; Albano, L.; Illuminati, F.

2007-01-01

We investigate continuous variable quantum teleportation using non-Gaussian states of the radiation field as entangled resources. We compare the performance of different classes of degaussified resources, including two-mode photon-added and two-mode photon-subtracted squeezed states. We then introduce a class of two-mode squeezed Bell-like states with one-parameter dependence for optimization. These states interpolate between and include as subcases different classes of degaussified resources. We show that optimized squeezed Bell-like resources yield a remarkable improvement in the fidelity of teleportation both for coherent and nonclassical input states. The investigation reveals that the optimal non-Gaussian resources for continuous variable teleportation are those that most closely realize the simultaneous maximization of the content of entanglement, the degree of affinity with the two-mode squeezed vacuum, and the, suitably measured, amount of non-Gaussianity

Epigenetic Loss of MLH1 Expression in Normal Human Hematopoietic Stem Cell Clones is Defined by the Promoter CpG Methylation Pattern Observed by High-Throughput Methylation Specific Sequencing.

Science.gov (United States)

Kenyon, Jonathan; Nickel-Meester, Gabrielle; Qing, Yulan; Santos-Guasch, Gabriela; Drake, Ellen; PingfuFu; Sun, Shuying; Bai, Xiaodong; Wald, David; Arts, Eric; Gerson, Stanton L

Normal human hematopoietic stem and progenitor cells (HPC) lose expression of MLH1 , an important mismatch repair (MMR) pathway gene, with age. Loss of MMR leads to replication dependent mutational events and microsatellite instability observed in secondary acute myelogenous leukemia and other hematologic malignancies. Epigenetic CpG methylation upstream of the MLH1 promoter is a contributing factor to acquired loss of MLH1 expression in tumors of the epithelia and proximal mucosa. Using single molecule high-throughput bisulfite sequencing we have characterized the CpG methylation landscape from -938 to -337 bp upstream of the MLH1 transcriptional start site (position +0), from 30 hematopoietic colony forming cell clones (CFC) either expressing or not expressing MLH1 . We identify a correlation between MLH1 promoter methylation and loss of MLH1 expression. Additionally, using the CpG site methylation frequencies obtained in this study we were able to generate a classification algorithm capable of sorting the expressing and non-expressing CFC. Thus, as has been previously described for many tumor cell types, we report for the first time a correlation between the loss of MLH1 expression and increased MLH1 promoter methylation in CFC derived from CD34 + selected hematopoietic stem and progenitor cells.

Protection of CpG ODN 1826 against radiation pulmonary fibrosis in rats

International Nuclear Information System (INIS)

Li Xuan; Qiao Tiankui; Zhuang Xibing; Zhang Jihong

2014-01-01

Objective: To explore the protectional function of CpG ODN 1826 against radiation pulmonary fibrosis in rats. Methods: The rat left lung was exposed to 20 Gy of 6 MV X-rays for establishing a radiation pulmonary fibrosis model. SD rats were randomly divided into control group, irradiated group and intervention group, with 30 rats in each group. CpG ODN 1826 was intraperitoneally injected into rats at 0, 1, 2, 5 and 7 d post-irradiation. The rats were terminated at 5, 15, 30 and 90 d post-irradiation, and the lung indexes were recorded. Paraffin sections of the radiated lung were conducted with HE staining and Masson staining, the pulmonary fibrosis scores were recorded. The serum concentrations of TGF-β1 and hydroxyproline (Hyp) were measured. Results: The radiation pulmonary fibrosis rat model was successfully established. The lung indexes of the control group were lower than those of the irradiated and intervention groups at 5 d post-irradiation (t = 3.046, 2.252, P < 0.05). The lung indexes of the intervention group were lower than those of the irradiated group (t = 4.120, 5.226, 5.719, P < 0.05). Pulmonary fibrosis scores of intervention group were lower than those of irradiated group (t = 3.212, 4.959, P < 0.05). The serum concentrations of TGF-β1 of irradiated group were higher than those of the intervention group (t = 4.138, 5.924, 4.138, 5.924, P < 0.05). The Hyp in the lung of irradiated group was higher than that of intervention group (t = 7.527, 8.416, P < 0.05). Conclusions: CpG ODN1826 will not worse the radiation pulmonary fibrosis, on the contrary, it could reduce the serum concentrations of TGF-β1 and the lung content of Hyp in radiation pulmonary fibrosis, and protects rat against radiation pulmonary fibrosis. (authors)

Association between the CpG island methylator phenotype and its prognostic significance in primary pulmonary adenocarcinoma.

Science.gov (United States)

Koh, Young Wha; Chun, Sung-Min; Park, Young-Soo; Song, Joon Seon; Lee, Geon Kook; Khang, Shin Kwang; Jang, Se Jin

2016-08-01

Aberrant methylation of promoter CpG islands is one of the most important inactivation mechanisms for tumor suppressor and tumor-related genes. Previous studies using genome-wide DNA methylation microarray analysis have suggested the existence of a CpG island methylator phenotype (CIMP) in lung adenocarcinomas. Although the biological behavior of these tumors varies according to tumor stage, no large-scale study has examined the CIMP in lung adenocarcinoma patients according to tumor stage. Furthermore, there have been no reported results regarding the clinical significance of each of the six CIMP markers. To examine the CIMP in patients with pulmonary adenocarcinoma after a surgical resection, we performed methylation analysis of six genes (CCNA1, ACAN, GFRA1, EDARADD, MGC45800, and p16 (INK4A)) in 230 pulmonary adenocarcinoma cases using the SEQUENOM MassARRAY platform. Fifty-four patients (28 %, 54/191) were in the CIMP-high (CIMP-H) group associated with high nodal stage (P = 0.007), the presence of micropapillary or solid histology (P = 0.003), and the absence of an epidermal growth factor receptor (EGFR) mutation (P = 0.002). By multivariate analysis, CIMP was an independent prognostic marker for overall survival (OS) and disease-specific survival (P = 0.03 and P = 0.43, respectively). In the stage I subgroups alone, CIMP-H patients had lower OS rates than the CIMP-low (CIMP-L) group (P = 0.041). Of the six CIMP markers, ACAN alone was significantly associated with patient survival. CIMP predicted the risk of progression independently of clinicopathological variables and enables the stratification of pulmonary adenocarcinoma patients, particularly among stage I cases.

Reduction of Non-stationary Noise using a Non-negative Latent Variable Decomposition

DEFF Research Database (Denmark)

Schmidt, Mikkel Nørgaard; Larsen, Jan

2008-01-01

We present a method for suppression of non-stationary noise in single channel recordings of speech. The method is based on a non-negative latent variable decomposition model for the speech and noise signals, learned directly from a noisy mixture. In non-speech regions an over complete basis...... is learned for the noise that is then used to jointly estimate the speech and the noise from the mixture. We compare the method to the classical spectral subtraction approach, where the noise spectrum is estimated as the average over non-speech frames. The proposed method significantly outperforms...

Characterization of human gastric carcinoma-related methylation of 9 miR CpG islands and repression of their expressions in vitro and in vivo

International Nuclear Information System (INIS)

Du, Yantao; Liu, Zhaojun; Gu, Liankun; Zhou, Jing; Zhu, Bu-dong; Ji, Jiafu; Deng, Dajun

2012-01-01

Many miR genes are located within or around CpG islands. It is unclear whether methylation of these CpG islands represses miR transcription regularly. The aims of this study are to characterize gastric carcinoma (GC)-related methylation of miR CpG islands and its relationship with miRNA expression. Methylation status of 9 representative miR CpG islands in a panel of cell lines and human gastric samples (including 13 normal biopsies, 38 gastritis biopsies, 112 pairs of GCs and their surgical margin samples) was analyzed by bisulfite-DHPLC and sequencing. Mature miRNA levels were determined with quantitative RT-PCR. Relationships between miR methylation, transcription, GC development, and clinicopathological characteristics were statistically analyzed. Methylation frequency of 5 miR CpG islands (miR-9-1, miR-9-3, miR-137, miR-34b, and miR-210) gradually increased while the proportion of methylated miR-200b gradually decreased during gastric carcinogenesis (Ps < 0.01). More miR-9-1 methylation was detected in 62%-64% of the GC samples and 4% of the normal or gastritis samples (18/28 versus 2/48; Odds ratio, 41.4; P < 0.01). miR-210 methylation showed high correlation with H. pylori infection. miR-375, miR-203, and miR-193b methylation might be host adaptation to the development of GCs. Methylation of these miR CpG islands was consistently shown to significantly decrease the corresponding miRNA levels presented in human cell lines. The inverse relationship was also observed for miR-9-1, miR-9-3, miR-137, and miR-200b in gastric samples. Among 112 GC patients, miR-9-1 methylation was an independent favourable predictor of overall survival of GC patients in both univariate and multivariate analysis (P < 0.02). In conclusion, alteration of methylation status of 6 of 9 tested miR CpG islands was characterized in gastric carcinogenesis. miR-210 methylation correlated with H. pylori infection. miR-9-1 methylation may be a GC-specific event. Methylation of miR CpG islands may

Acting on social exclusion: neural correlates of punishment and forgiveness of excluders.

Science.gov (United States)

Will, Geert-Jan; Crone, Eveline A; Güroğlu, Berna

2015-02-01

This functional magnetic resonance imaging study examined the neural correlates of punishment and forgiveness of initiators of social exclusion (i.e. 'excluders'). Participants divided money in a modified Dictator Game between themselves and people who previously either included or excluded them during a virtual ball-tossing game (Cyberball). Participants selectively punished the excluders by decreasing their outcomes; even when this required participants to give up monetary rewards. Punishment of excluders was associated with increased activation in the pre-supplementary motor area (pre-SMA) and bilateral anterior insula. Costly punishment was accompanied by higher activity in the pre-SMA compared with punishment that resulted in gains or was non-costly. Refraining from punishment (i.e. forgiveness) was associated with self-reported perspective-taking and increased activation in the bilateral temporoparietal junction, dorsomedial prefrontal cortex, dorsal anterior cingulate cortex, and ventrolateral and dorsolateral prefrontal cortex. These findings show that social exclusion can result in punishment as well as forgiveness of excluders and that separable neural networks implicated in social cognition and cognitive control are recruited when people choose either to punish or to forgive those who excluded them. © The Author (2014). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

Nicotine induced CpG methylation of Pax6 binding motif in StAR promoter reduces the gene expression and cortisol production

International Nuclear Information System (INIS)

Wang, Tingting; Chen, Man; Liu, Lian; Cheng, Huaiyan; Yan, You-E; Feng, Ying-Hong; Wang, Hui

2011-01-01

Steroidogenic acute regulatory protein (StAR) mediates the rate-limiting step in the synthesis of steroid hormones, essential to fetal development. We have reported that the StAR expression in fetal adrenal is inhibited in a rat model of nicotine-induced intrauterine growth retardation (IUGR). Here using primary human fetal adrenal cortex (pHFAC) cells and a human fetal adrenal cell line NCI-H295A, we show that nicotine inhibits StAR expression and cortisol production in a dose- and time-dependent manner, and prolongs the inhibitory effect on cells proliferating over 5 passages after termination of nicotine treatment. Methylation detection within the StAR promoter region uncovers a single site CpG methylation at nt -377 that is sensitive to nicotine treatment. Nicotine-induced alterations in frequency of this point methylation correlates well with the levels of StAR expression, suggesting an important role of the single site in regulating StAR expression. Further studies using bioinformatics analysis and siRNA approach reveal that the single CpG site is part of the Pax6 binding motif (CGCCTGA) in the StAR promoter. The luciferase activity assays validate that Pax6 increases StAR gene expression by binding to the glucagon G3-like motif (CGCCTGA) and methylation of this site blocks Pax6 binding and thus suppresses StAR expression. These data identify a nicotine-sensitive CpG site at the Pax6 binding motif in the StAR promoter that may play a central role in regulating StAR expression. The results suggest an epigenetic mechanism that may explain how nicotine contributes to onset of adult diseases or disorders such as metabolic syndrome via fetal programming. -- Highlights: ► Nicotine-induced StAR inhibition in two human adrenal cell models. ► Nicotine-induced single CpG site methylation in StAR promoter. ► Persistent StAR inhibition and single CpG methylation after nicotine termination. ► Single CpG methylation located at Pax6 binding motif regulates St

Proinflammatory Stimulation of Toll-Like Receptor 9 with High Dose CpG ODN 1826 Impairs Endothelial Regeneration and Promotes Atherosclerosis in Mice.

Directory of Open Access Journals (Sweden)

Alexander O Krogmann

Full Text Available Toll-like receptors (TLR of the innate immune system have been closely linked with the development of atherosclerotic lesions. TLR9 is activated by unmethylated CpG motifs within ssDNA, but also by CpG motifs in nucleic acids released during vascular apoptosis and necrosis. The role of TLR9 in vascular disease remains controversial and we sought to investigate the effects of a proinflammatory TLR9 stimulation in mice.TLR9-stimulation with high dose CpG ODN at concentrations between 6.25 nM to 30 nM induced a significant proinflammatory cytokine response in mice. This was associated with impaired reendothelialization upon acute denudation of the carotid and increased numbers of circulating endothelial microparticles, as a marker for amplified endothelial damage. Chronic TLR9 agonism in apolipoprotein E-deficient (ApoE-/- mice fed a cholesterol-rich diet increased aortic production of reactive oxygen species, the number of circulating endothelial microparticles, circulating sca-1/flk-1 positive cells, and most importantly augmented atherosclerotic plaque formation when compared to vehicle treated animals. Importantly, high concentrations of CpG ODN are required for these proatherogenic effects.Systemic stimulation of TLR9 with high dose CpG ODN impaired reendothelialization upon acute vascular injury and increased atherosclerotic plaque development in ApoE-/- mice. Further studies are necessary to fully decipher the contradictory finding of TLR9 agonism in vascular biology.

CpG ODN 1668 induce innate and adaptive immune responses in rock bream (Oplegnathus fasciatus) against rock bream iridovirus (RBIV) infection.

Science.gov (United States)

Jung, Myung-Hwa; Jung, Sung-Ju

2017-10-01

Rock bream iridovirus (RBIV) causes severe mass mortalities in rock bream in Korea. CpG ODN 1668 showed promise as immunoprotective agents against RBIV infection in rock bream. In this study, we assessed innate/adaptive-related gene expression patterns in RBIV-infected rock bream with and without CpG ODN 1668 administration to determine important immune defense related factors that may affect fish survival. In the CpG ODN 1668+virus-injected group, virus copies were more than 7.4- to 790591-fold lower than in the virus-injected group at 4 d (8.79 × 10 4 and 6.58 × 10 5 /μl, respectively), 7 d (5.30 × 10 2 and 2.29 × 10 7 /μl, respectively) and 10 dpi (7.79 × 10 1 and 6.16 × 10 7 /μl, respectively). Furthermore, in the CpG ODN 1668+virus-injected group, significantly higher levels of MyD88 (6 h, 1 d, 4 d and 7 dpi), IL1β (1 d, 2 d and 7 dpi) and perforin/granzyme (1 dpi) expression were observed, whereas these genes were not significantly expressed in the virus-injected group at that time points. Mx, ISG15 and PKR were significantly highly expressed at 4 d and 7 dpi and reduced when low viral loads at 10 dpi in the CpG ODN 1668+virus-injected group. Conversely, in the virus-injected group, Mx, ISG15 and PKR expression were significantly higher than the control group until 10 dpi. However, MHC class I, CD8, Fas, Fas ligand and caspases (3, 8 and 9) expression levels showed no statistically significant differences between virus- and CpG ODN 1668+virus-injected group. In summary, CpG ODN 1668 administration in fish induces innate immune response or cell death pathway, which could be a major contributing factor to effective fish control over viral transcription on 4 d to 10 dpi. Expression of MyD88, IL1β, perforin and granzyme-related immune gene response is critical factor for inhibition of RBIV replication. Copyright © 2017 Elsevier Ltd. All rights reserved.

42 CFR 409.49 - Excluded services.

Science.gov (United States)

2010-10-01

... HOSPITAL INSURANCE BENEFITS Home Health Services Under Hospital Insurance § 409.49 Excluded services. (a... individual's dialysis, are excluded from coverage under the Medicare home health benefit. (f) Prosthetic... 42 Public Health 2 2010-10-01 2010-10-01 false Excluded services. 409.49 Section 409.49 Public...

24 CFR 3280.7 - Excluded structures.

Science.gov (United States)

2010-04-01

... 24 Housing and Urban Development 5 2010-04-01 2010-04-01 false Excluded structures. 3280.7 Section... DEVELOPMENT MANUFACTURED HOME CONSTRUCTION AND SAFETY STANDARDS General § 3280.7 Excluded structures. Certain structures may be excluded from these Standards as modular homes under 24 CFR 3282.12. [52 FR 4581, Feb. 12...

Non-linear frequency response of non-isothermal adsorption controlled by micropore diffusion with variable diffusivity

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MENKA PETKOVSKA

2000-12-01

Full Text Available The concept of higher order frequency response functions (FRFs is used for the analysis of non-linear adsorption kinetics on a particle scale, for the case of non-isothermal micropore diffusion with variable diffusivity. Six series of FRFs are defined for the general non-isothermal case. A non-linerar mathematical model is postulated and the first and second order FRFs derived and simulated. A variable diffusivity influences the shapes of the second order FRFs relating the sorbate concentration in the solid phase and t he gas pressure significantly, but they still keep their characteristics which can be used for discrimination of this from other kinetic mechanisms. It is also shown that first and second order particle FRFs offter sufficient information for an easy and fast estimation of all model parameters, including those defining the system non-linearity.

Prognostication of patients with clear cell renal cell carcinomas based on quantification of DNA methylation levels of CpG island methylator phenotype marker genes.

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Tian, Ying; Arai, Eri; Gotoh, Masahiro; Komiyama, Motokiyo; Fujimoto, Hiroyuki; Kanai, Yae

2014-10-20

The CpG island methylator phenotype (CIMP) of clear cell renal cell carcinomas (ccRCCs) is characterized by accumulation of DNA methylation at CpG islands and poorer patient outcome. The aim of this study was to establish criteria for prognostication of patients with ccRCCs using the ccRCC-specific CIMP marker genes. DNA methylation levels at 299 CpG sites in the 14 CIMP marker genes were evaluated quantitatively in tissue specimens of 88 CIMP-negative and 14 CIMP-positive ccRCCs in a learning cohort using the MassARRAY system. An additional 100 ccRCCs were also analyzed as a validation cohort. Receiver operating characteristic curve analysis showed that area under the curve values for the 23 CpG units including the 32 CpG sites in the 7 CIMP-marker genes, i.e. FAM150A, ZNF540, ZNF671, ZNF154, PRAC, TRH and SLC13A5, for discrimination of CIMP-positive from CIMP-negative ccRCCs were larger than 0.95. Criteria combining the 23 CpG units discriminated CIMP-positive from CIMP-negative ccRCCs with 100% sensitivity and specificity in the learning cohort. Cancer-free and overall survival rates of patients with CIMP-positive ccRCCs diagnosed using the criteria combining the 23 CpG units in a validation cohort were significantly lower than those of patients with CIMP-negative ccRCCs (P = 1.41 × 10-5 and 2.43 × 10-13, respectively). Patients with CIMP-positive ccRCCs in the validation cohort had a higher likelihood of disease-related death (hazard ratio, 75.8; 95% confidence interval, 7.81 to 735; P = 1.89 × 10-4) than those with CIMP-negative ccRCCs. The established criteria are able to reproducibly diagnose CIMP-positive ccRCCs and may be useful for personalized medicine for patients with ccRCCs.

78 FR 28904 - CPG Carlyle Private Equity Fund, LLC, et al.; Notice of Application

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2013-05-16

... as Delaware limited liability companies. The Feeder Fund operates as a feeder fund in a master-feeder..., and mezzanine). 2. The Adviser, a Delaware limited liability company and wholly- owned subsidiary of... SECURITIES AND EXCHANGE COMMISSION [Investment Company Act Release No. 30512; 812-14089] CPG...

Nicotine induced CpG methylation of Pax6 binding motif in StAR promoter reduces the gene expression and cortisol production

Energy Technology Data Exchange (ETDEWEB)

Wang, Tingting [Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071 (China); Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, Maryland (United States); Chen, Man; Liu, Lian [Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071 (China); Cheng, Huaiyan [Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, Maryland (United States); Yan, You-E [Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071 (China); Feng, Ying-Hong, E-mail: yhfeng@usuhs.edu [Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, Maryland (United States); Wang, Hui, E-mail: wanghui19@whu.edu.cn [Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071 (China); Research Center of Food and Drug Evaluation, Wuhan University, Wuhan 430071 (China)

2011-12-15

Steroidogenic acute regulatory protein (StAR) mediates the rate-limiting step in the synthesis of steroid hormones, essential to fetal development. We have reported that the StAR expression in fetal adrenal is inhibited in a rat model of nicotine-induced intrauterine growth retardation (IUGR). Here using primary human fetal adrenal cortex (pHFAC) cells and a human fetal adrenal cell line NCI-H295A, we show that nicotine inhibits StAR expression and cortisol production in a dose- and time-dependent manner, and prolongs the inhibitory effect on cells proliferating over 5 passages after termination of nicotine treatment. Methylation detection within the StAR promoter region uncovers a single site CpG methylation at nt -377 that is sensitive to nicotine treatment. Nicotine-induced alterations in frequency of this point methylation correlates well with the levels of StAR expression, suggesting an important role of the single site in regulating StAR expression. Further studies using bioinformatics analysis and siRNA approach reveal that the single CpG site is part of the Pax6 binding motif (CGCCTGA) in the StAR promoter. The luciferase activity assays validate that Pax6 increases StAR gene expression by binding to the glucagon G3-like motif (CGCCTGA) and methylation of this site blocks Pax6 binding and thus suppresses StAR expression. These data identify a nicotine-sensitive CpG site at the Pax6 binding motif in the StAR promoter that may play a central role in regulating StAR expression. The results suggest an epigenetic mechanism that may explain how nicotine contributes to onset of adult diseases or disorders such as metabolic syndrome via fetal programming. -- Highlights: Black-Right-Pointing-Pointer Nicotine-induced StAR inhibition in two human adrenal cell models. Black-Right-Pointing-Pointer Nicotine-induced single CpG site methylation in StAR promoter. Black-Right-Pointing-Pointer Persistent StAR inhibition and single CpG methylation after nicotine termination

Distribution of CpG Motifs in Upstream Gene Domains in a Reef Coral and Sea Anemone: Implications for Epigenetics in Cnidarians.

Science.gov (United States)

Marsh, Adam G; Hoadley, Kenneth D; Warner, Mark E

2016-01-01

Coral reefs are under assault from stressors including global warming, ocean acidification, and urbanization. Knowing how these factors impact the future fate of reefs requires delineating stress responses across ecological, organismal and cellular scales. Recent advances in coral reef biology have integrated molecular processes with ecological fitness and have identified putative suites of temperature acclimation genes in a Scleractinian coral Acropora hyacinthus. We wondered what unique characteristics of these genes determined their coordinate expression in response to temperature acclimation, and whether or not other corals and cnidarians would likewise possess these features. Here, we focus on cytosine methylation as an epigenetic DNA modification that is responsive to environmental stressors. We identify common conserved patterns of cytosine-guanosine dinucleotide (CpG) motif frequencies in upstream promoter domains of different functional gene groups in two cnidarian genomes: a coral (Acropora digitifera) and an anemone (Nematostella vectensis). Our analyses show that CpG motif frequencies are prominent in the promoter domains of functional genes associated with environmental adaptation, particularly those identified in A. hyacinthus. Densities of CpG sites in upstream promoter domains near the transcriptional start site (TSS) are 1.38x higher than genomic background levels upstream of -2000 bp from the TSS. The increase in CpG usage suggests selection to allow for DNA methylation events to occur more frequently within 1 kb of the TSS. In addition, observed shifts in CpG densities among functional groups of genes suggests a potential role for epigenetic DNA methylation within promoter domains to impact functional gene expression responses in A. digitifera and N. vectensis. Identifying promoter epigenetic sequence motifs among genes within specific functional groups establishes an approach to describe integrated cellular responses to environmental stress in

Distribution of CpG Motifs in Upstream Gene Domains in a Reef Coral and Sea Anemone: Implications for Epigenetics in Cnidarians.

Directory of Open Access Journals (Sweden)

Adam G Marsh

Full Text Available Coral reefs are under assault from stressors including global warming, ocean acidification, and urbanization. Knowing how these factors impact the future fate of reefs requires delineating stress responses across ecological, organismal and cellular scales. Recent advances in coral reef biology have integrated molecular processes with ecological fitness and have identified putative suites of temperature acclimation genes in a Scleractinian coral Acropora hyacinthus. We wondered what unique characteristics of these genes determined their coordinate expression in response to temperature acclimation, and whether or not other corals and cnidarians would likewise possess these features. Here, we focus on cytosine methylation as an epigenetic DNA modification that is responsive to environmental stressors. We identify common conserved patterns of cytosine-guanosine dinucleotide (CpG motif frequencies in upstream promoter domains of different functional gene groups in two cnidarian genomes: a coral (Acropora digitifera and an anemone (Nematostella vectensis. Our analyses show that CpG motif frequencies are prominent in the promoter domains of functional genes associated with environmental adaptation, particularly those identified in A. hyacinthus. Densities of CpG sites in upstream promoter domains near the transcriptional start site (TSS are 1.38x higher than genomic background levels upstream of -2000 bp from the TSS. The increase in CpG usage suggests selection to allow for DNA methylation events to occur more frequently within 1 kb of the TSS. In addition, observed shifts in CpG densities among functional groups of genes suggests a potential role for epigenetic DNA methylation within promoter domains to impact functional gene expression responses in A. digitifera and N. vectensis. Identifying promoter epigenetic sequence motifs among genes within specific functional groups establishes an approach to describe integrated cellular responses to

B-CLL cells acquire APC- and CTL-like phenotypic characteristics after stimulation with CpG ODN and IL-21

Science.gov (United States)

Hagn, Magdalena; Blackwell, Sue E.; Beyer, Thamara; Ebel, Verena; Fabricius, Dorit; Lindner, Stefanie; Stilgenbauer, Stefan; Simmet, Thomas; Tam, Constantine; Neeson, Paul; Trapani, Joseph A.; Schrezenmeier, Hubert; Weiner, George J.

2014-01-01

CpG oligodeoxynucleotides (CpG) and IL-21 are two promising agents for the treatment of B-cell chronic lymphocytic leukemia (B-CLL). Recently, we reported that the combination of CpG and IL-21 (CpG/IL-21) can induce granzyme B (GrB)-dependent apoptosis in B-CLL cells. Here, we demonstrate that treatment of B-CLL cells with CpG and IL-21 results in the development of antigen-presenting cell (APC)-like cells with cytotoxic features. These properties eventually give rise to B-CLL cell apoptosis, independently of their cytogenetic phenotype, whereas normal B-cell survival is not negatively affected by CpG/IL-21. APC- and CTL-typical molecules found to be up-regulated in CpG/IL-21-stimulated B-CLL cells include GrB, perforin, T-bet, monokine-induced by IFN-γ and IFN-γ-inducible protein 10 (IP-10), as well as molecules important for cell adhesion, antigen cross-presentation and costimulation. Also induced are molecules involved in GrB induction, trafficking and processing, whereas the GrB inhibitor Serpin B9 [formerly proteinase inhibitor-9 (PI-9)] is down-modulated by CpG/IL-21. In conclusion, CpG/IL-21-stimulated B-CLL cells acquire features that are reminiscent of killer dendritic cells, and which result in enhanced immunogenicity, cytotoxicity and apoptosis. Our results provide novel insights into the aberrant immune state of B-CLL cells and may establish a basis for the development of an innovative cellular vaccination approach in B-CLL. PMID:24497611

Determinants of Prosocial Behavior in Included Versus Excluded Contexts.

Science.gov (United States)

Cuadrado, Esther; Tabernero, Carmen; Steinel, Wolfgang

2015-01-01

Prosocial behavior (PSB) is increasingly becoming necessary as more and more individuals experience exclusion. In this context it is important to understand the motivational determinants of PSB. Here we report two experiments which analyzed the influence of dispositional (prosocialness; rejection sensitivity) and motivational variables (prosocial self-efficacy; prosocial collective efficacy; trust; anger; social affiliation motivation) on PSB under neutral contexts (Study 1), and once under inclusion or exclusion conditions (Study 2). Both studies provided evidence for the predicted mediation of PSB. Results in both neutral and inclusion and exclusion conditions supported our predictive model of PSB. In the model dispositional variables predicted motivational variables, which in turn predicted PSB. We showed that the investigated variables predicted PSB; this suggests that to promote PSB one could (1) foster prosocialness, prosocial self and collective efficacy, trust in others and affiliation motivation and (2) try to reduce negative feelings and the tendency to dread rejection in an attempt to reduce the negative impact that these variables have on PSB. Moreover, the few differences that emerged in the model between the inclusion and exclusion contexts suggested that in interventions with excluded individuals special care emphasis should be placed on addressing rejection sensitivity and lack of trust.

Determinants of prosocial behavior in included versus excluded contexts

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Esther eCuadrado

2016-01-01

Full Text Available Prosocial behavior is increasingly becoming necessary as more and more individuals experience exclusion. In this context it is important to understand the motivational determinants of prosocial behavior. Here we report two experiments which analyzed the influence of dispositional (prosocialness; rejection sensitivity and motivational variables (prosocial self-efficacy; prosocial collective efficacy; trust; anger; social affiliation motivation on prosocial behavior under neutral contexts (Study 1, and once under inclusion or exclusion conditions (Study 2. Both studies provided evidence for the predicted mediation of prosocial behavior. Results in both neutral and inclusion and exclusion conditions supported our predictive model of prosocial behavior. In the model dispositional variables predicted motivational variables, which in turn predicted prosocial behavior. We showed that the investigated variables predicted prosocial behavior; this suggests that to promote prosocial behavior one could (1 foster prosocialness, prosocial self and collective efficacy, trust in others and affiliation motivation and (2 try to reduce negative feelings and the tendency to dread rejection in an attempt to reduce the negative impact that these variables have on prosocial behavior. Moreover, the few differences that emerged in the model between the inclusion and exclusion contexts suggested that in interventions with excluded individuals special care emphasis should be placed on addressing rejection sensitivity and lack of trust.

Non-Steroidal Anti-Inflammatory Drug Use and Genomic DNA Methylation in Blood.

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Lauren E Wilson

Full Text Available Non-steroidal anti-inflammatory drug (NSAID use is associated with decreased risk of some cancers. NSAID use modulates the epigenetic profile of normal colonic epithelium and may reduce risk of colon cancer through this pathway; however, the effect of NSAID use on the DNA methylation profile of other tissues including whole blood has not yet been examined.Using the Sister Study cohort, we examined the association between NSAID usage and whole genome methylation patterns in blood DNA. Blood DNA methylation status across 27,589 CpG sites was evaluated for 871 women using the Illumina Infinium HumanMethylation27 Beadchip, and in a non-overlapping replication sample of 187 women at 485,512 CpG sites using the Infinium HumanMethylation450 Beadchip. We identified a number of CpG sites that were differentially methylated in regular, long-term users of NSAIDs in the discovery group, but none of these sites were statistically significant in our replication group.We found no replicable methylation differences in blood related to NSAID usage. If NSAID use does effect blood DNA methylation patterns, differences are likely small.

Tumor vaccine composed of C-class CpG oligodeoxynucleotides and irradiated tumor cells induces long-term antitumor immunity

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Cerkovnik Petra

2010-09-01

Full Text Available Abstract Background An ideal tumor vaccine should activate both effector and memory immune response against tumor-specific antigens. Beside the CD8+ T cells that play a central role in the generation of a protective immune response and of long-term memory, dendritic cells (DCs are important for the induction, coordination and regulation of the adaptive immune response. The DCs can conduct all of the elements of the immune orchestra and are therefore a fundamental target and tool for vaccination. The present study was aimed at assessing the ability of tumor vaccine composed of C-class CpG ODNs and irradiated melanoma tumor cells B16F1 followed by two additional injections of CpG ODNs to induce the generation of a functional long-term memory response in experimental tumor model in mice (i.p. B16F1. Results It has been shown that the functional memory response in vaccinated mice persists for at least 60 days after the last vaccination. Repeated vaccination also improves the survival of experimental animals compared to single vaccination, whereas the proportion of animals totally protected from the development of aggressive i.p. B16F1 tumors after vaccination repeated three times varies between 88.9%-100.0%. Additionally, the long-term immune memory and tumor protection is maintained over a prolonged period of time of at least 8 months. Finally, it has been demonstrated that following the vaccination the tumor-specific memory cells predominantly reside in bone marrow and peritoneal tissue and are in a more active state than their splenic counterparts. Conclusions In this study we demonstrated that tumor vaccine composed of C-class CpG ODNs and irradiated tumor cells followed by two additional injections of CpG ODNs induces a long-term immunity against aggressive B16F1 tumors.

A cross-study analysis of prenatal exposures to environmental contaminants and the epigenome: support for stress-responsive transcription factor occupancy as a mediator of gene-specific CpG methylation patterning

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Martin, Elizabeth M.; Fry, Rebecca C.

2016-01-01

Abstract A biological mechanism by which exposure to environmental contaminants results in gene-specific CpG methylation patterning is currently unknown. We hypothesize that gene-specific CpG methylation is related to environmentally perturbed transcription factor occupancy. To test this hypothesis, a database of 396 genes with altered CpG methylation either in cord blood leukocytes or placental tissue was compiled from 14 studies representing assessments of six environmental contaminants. Subsequently, an in silico approach was used to identify transcription factor binding sites enriched among the genes with altered CpG methylation in relationship to the suite of environmental contaminants. For each study, the sequences of the promoter regions (representing −1000 to +500 bp from the transcription start site) of all genes with altered CpG methylation were analyzed for enrichment of transcription factor binding sites. Binding sites for a total of 56 unique transcription factors were identified to be enriched within the promoter regions of the genes. Binding sites for the Kidney-Enriched Krupple-like Factor 15, a known responder to endogenous stress, were enriched ( P  contaminants. These data support the transcription factor occupancy theory as a potential mechanism underlying environmentally-induced gene-specific CpG methylation. PMID:27066266

Gene Silencing Triggers Polycomb Repressive Complex 2 Recruitment to CpG Islands Genome Wide

DEFF Research Database (Denmark)

Riising, Eva Madi; Vacher-Comet, Itys; Leblanc, Benjamin Olivier

2014-01-01

-wide ectopic PRC2 recruitment to endogenous PcG target genes found in other tissues. PRC2 binding analysis shows that it is restricted to nucleosome-free CpG islands (CGIs) of untranscribed genes. Our results show that it is the transcriptional state that governs PRC2 binding, and we propose that it binds...

Short- and long-term variations in non-linear dynamics of heart rate variability

DEFF Research Database (Denmark)

Kanters, J K; Højgaard, M V; Agner, E

1996-01-01

OBJECTIVES: The purpose of the study was to investigate the short- and long-term variations in the non-linear dynamics of heart rate variability, and to determine the relationships between conventional time and frequency domain methods and the newer non-linear methods of characterizing heart rate...... rate and describes mainly linear correlations. Non-linear predictability is correlated with heart rate variability measured as the standard deviation of the R-R intervals and the respiratory activity expressed as power of the high-frequency band. The dynamics of heart rate variability changes suddenly...

CpG island methylation phenotype (CIMP) in oral cancer: associated with a marked inflammatory response and less aggressive tumour biology.

Science.gov (United States)

Shaw, Richard J; Hall, Gillian L; Lowe, Derek; Bowers, Naomi L; Liloglou, Triantafillos; Field, John K; Woolgar, Julia A; Risk, Janet M

2007-10-01

Studies in several tumour sites highlight the significance of the CpG island methylation phenotype (CIMP), with distinct features of histology, biological aggression and outcome. We utilise pyrosequencing techniques of quantitative methylation analysis to investigate the presence of CIMP in oral squamous cell carcinoma (OSCC) for the first time, and evaluate its correlation with allelic imbalance, pathology and clinical behaviour. Tumour tissue, control tissue and PBLs were obtained from 74 patients with oral squamous cell carcinoma. Pyrosequencing was used to analyse methylation patterns in 75-200 bp regions of the CpG rich gene promoters of 10 genes with a broad range of cellular functions. Allelic imbalance was investigated using a multiplexed panel of 11 microsatellite markers. Corresponding variables, histopathological staging and grading were correlated with these genetic and epigenetic aberrations. A cluster of tumours with a greater degree of promoter methylation than would be predicted by chance alone (P=0.001) were designated CIMP+ve. This group had less aggressive tumour biology in terms of tumour thickness (p=0.015) and nodal metastasis (P=0.012), this being apparently independent of tumour diameter. Further, it seems that these CIMP+ve tumours excited a greater host inflammatory response (P=0.019). The exact mechanisms underlying CIMP remain obscure but the association with a greater inflammatory host response supports existing theories relating these features in other tumour sites. As CIMP has significant associations with other well documented prognostic indicators, it may prove beneficial to include methylation analyses in molecular risk modelling of tumours.

Regulatory domain or CpG site variation in SLC12A5, encoding the chloride transporter KCC2, in human autism and schizophrenia

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Nancy D Merner

2015-10-01

Full Text Available Many encoded gene products responsible for neurodevelopmental disorders (NDs like autism spectrum disorders (ASD, schizophrenia (SCZ, intellectual disability (ID, and idiopathic generalized epilepsy (IGE converge on networks controlling synaptic function. An increase in KCC2 (SLC12A5 Cl- transporter activity drives the developmental GABA excitatory-inhibitory sequence, but the role of KCC2 in human NDs is essentially unknown. Here, we report two rare, non-synonymous (NS, functionally-impairing variants in the KCC2 C-terminal regulatory domain (CTRD in human ASD (R952H and R1049C and SCZ (R952H previously linked with IGE and familial febrile seizures, and another novel NS KCC2 variant in ASD (R1048W with highly-predicted pathogenicity. Exome data from 2517 simplex families in the ASD Simon Simplex Collection revealed significantly more KCC2 CTRD variants in ASD cases than controls, and interestingly, these were more often synonymous and predicted to disrupt or introduce a CpG site. Furthermore, full gene analysis showed ASD cases are more likely to contain rare KCC2 variants affecting CpG sites than controls. These data suggest genetically-encoded dysregulation of KCC2-dependent GABA signaling may contribute to multiple human NDs.

Addressing dichotomous data for participants excluded from trial analysis: a guide for systematic reviewers.

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Elie A Akl

Full Text Available Systematic reviewer authors intending to include all randomized participants in their meta-analyses need to make assumptions about the outcomes of participants with missing data.The objective of this paper is to provide systematic reviewer authors with a relatively simple guidance for addressing dichotomous data for participants excluded from analyses of randomized trials.This guide is based on a review of the Cochrane handbook and published methodological research. The guide deals with participants excluded from the analysis who were considered 'non-adherent to the protocol' but for whom data are available, and participants with missing data.Systematic reviewer authors should include data from 'non-adherent' participants excluded from the primary study authors' analysis but for whom data are available. For missing, unavailable participant data, authors may conduct a complete case analysis (excluding those with missing data as the primary analysis. Alternatively, they may conduct a primary analysis that makes plausible assumptions about the outcomes of participants with missing data. When the primary analysis suggests important benefit, sensitivity meta-analyses using relatively extreme assumptions that may vary in plausibility can inform the extent to which risk of bias impacts the confidence in the results of the primary analysis. The more plausible assumptions draw on the outcome event rates within the trial or in all trials included in the meta-analysis. The proposed guide does not take into account the uncertainty associated with assumed events.This guide proposes methods for handling participants excluded from analyses of randomized trials. These methods can help in establishing the extent to which risk of bias impacts meta-analysis results.

High CpG island methylation ofp16 gene and loss of p16 protein ...

Indian Academy of Sciences (India)

Navya

employed to detect CpG island methylation in p16 promoter region and ... of Fallot;p16 gene;p16 protein;CpG islands;Methylation;Promoter regions ..... Our findings that p16 has a role in heart development is ... Asian Pac J Cancer Prev 15, 75-84. .... phenotype in colorectal cancer using a large population-based sample.

Nucleosomes correlate with in vivo progression pattern of de novo methylation of p16 CpG islands in human gastric carcinogenesis.

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Zhe-Ming Lu

Full Text Available BACKGROUND: The exact relationship between nucleosome positioning and methylation of CpG islands in human pathogenesis is unknown. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we characterized the nucleosome position within the p16 CpG island and established a seeding methylation-specific PCR (sMSP assay based on bisulfite modification to enrich the p16 alleles containing methylated-CpG at the methylation "seeding" sites within its intron-1 in gastric carcinogenesis. The sMSP-positive rate in primary gastric carcinoma (GC samples (36/40 was significantly higher than that observed in gastritis (19/45 or normal samples (7/13 (P<0.01. Extensive clone sequencing of these sMSP products showed that the density of methylated-CpGs in p16 CpG islands increased gradually along with the severity of pathological changes in gastric tissues. In gastritis lesions the methylation was frequently observed in the region corresponding to the exon-1 coding-nucleosome and the 5'UTR-nucleosome; the methylation was further extended to the region corresponding to the promoter-nucleosome in GC samples. Only few methylated-CpG sites were randomly detected within p16 CpG islands in normal tissues. The significantly inversed relationship between the p16 exon-1 methylation and its transcription was observed in GC samples. An exact p16 promoter-specific 83 bp-MSP assay confirms the result of sMSP (33/55 vs. 1/6, P<0.01. In addition, p16 methylation in chronic gastritis lesions significantly correlated with H. pylori infection; however, such correlation was not observed in GC specimens. CONCLUSIONS/SIGNIFICANCE: It was determined that de novo methylation was initiated in the coding region of p16 exon-1 in gastritis, then progressed to its 5'UTR, and ultimately to the proximal promoter in GCs. Nucleosomes may function as the basic extension/progression unit of de novo methylation of p16 CpG islands in vivo.

High CpG island methylation of p16 gene and loss of p16 protein

Indian Academy of Sciences (India)

Methylation-specific polymerase chain reaction (MSP) was employed to detect CpG island methylation in p16 promoter region andWestern blotting was used to detect p16 expression of all subjects. Real-time fluorescence quantitative polymerase chain reaction (FQ-PCR) was performed to test p16 mRNA expression.

NIKEI: a new inexpensive and non-invasive scoring system to exclude advanced fibrosis in patients with NAFLD.

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Münevver Demir

Full Text Available AIMS: To develop, validate and compare a non-invasive fibrosis scoring system for non-alcoholic fatty liver disease (NAFLD derived from routinely obtained clinical and biochemical parameters. METHODS: 267 consecutive patients with biopsy proven fatty liver or non-alcoholic steatohepatitis were randomly assigned to the estimation (2/3 or validation (1/3 group to develop a model for the prediction of advanced fibrosis. Univariate statistics were performed to compare patients with and without advanced fibrosis, and following a multivariate logistic regression analysis a new scoring system was constructed. This non-invasive Koeln-Essen-index (NIKEI was validated and compared to the FIB-4 index by calculating the area under the receiver operating characteristic curve (AUC. We evaluated a stepwise combination of both scoring systems for the precise prediction of advanced fibrosis. To set in contrast, we additionally tested the diagnostic accuracy of the AST/ALT ratio, BARD score and the NAFLD fibrosis score in our cohort. RESULTS: Age, AST, AST/ALT ratio, and total bilirubin were identified as significant predictors of advanced fibrosis and used to construct the NIKEI with an AUC of 0.968 [0.937; 0.998] compared to 0.929 [0.869; 0.989] for the FIB-4 index. The absence of advanced fibrosis could be confirmed with excellent accuracy (99-100%. The positive predictive value of the FIB-4 index was higher (100% vs. 60%, however, the false negative rate was also high (33%. With a stepwise combination of both indices 82%-84% of biopsies would have been avoidable without a single misclassification. The AUROC for AST/ALT ratio, the NAFLD fibrosis score, and the BARD score were 0.81 (95% CI, 0.72-0.90, 0.96 (95% CI 0.92-0.99, and 0.67 (95% CI 0.55-0.78, respectively. CONCLUSION: The NIKEI can reliably exclude advanced fibrosis in subjects with NAFLD. In combination with the FIB-4 index misclassification with inadequate clinical management can be avoided while

A novel method to quantify local CpG methylation density by regional methylation elongation assay on microarray

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Qiao Yingjuan

2008-01-01

Full Text Available Abstract Background DNA methylation based techniques are important tools in both clinical diagnostics and therapeutics. But most of these methods only analyze a few CpG sites in a target region. Indeed, difference of site-specific methylation may also lead to a change of methylation density in many cases, and it has been found that the density of methylation is more important than methylation of single CpG site for gene silencing. Results We have developed a novel approach for quantitative analysis of CpG methylation density on the basis of microarray-based hybridization and incorporation of Cy5-dCTP into the Cy3 labeled target DNA by using Taq DNA Polymerase on microarray. The quantification is achieved by measuring Cy5/Cy3 signal ratio which is proportional to methylation density. This methylation-sensitive technique, termed RMEAM (regional methylation elongation assay on microarray, provides several advantages over existing methods used for methylation analysis. It can determine an exact methylation density of the given region, and has potential of high throughput. We demonstrate a use of this method in determining the methylation density of the promoter region of the tumor-related gene MLH1, TERT and MGMT in colorectal carcinoma patients. Conclusion This technique allows for quantitative analysis of regional methylation density, which is the representative of all allelic methylation patterns in the sample. The results show that this technique has the characteristics of simplicity, rapidness, specificity and high-throughput.

High CpG island methylation of p16 gene and loss of p16 protein ...

Indian Academy of Sciences (India)

SI-JU GAO

The study subjects consisted of 75 healthy controls and 63 ToF ... Additionally, our analysis suggested that CpG island methylation in p16 promoters in ToF ..... reduced p16 protein expression in lung cancer (Kondo et al. 2006). In this context ..... promoter methylation in gastric carcinogenesis: a meta-analysis. Mol. Biol. Rep.

7 CFR 58.137 - Excluded milk.

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2010-01-01

... 7 Agriculture 3 2010-01-01 2010-01-01 false Excluded milk. 58.137 Section 58.137 Agriculture... Milk § 58.137 Excluded milk. A plant shall not accept milk from a producer if: (a) The milk has been in...) Three of the last five milk samples have exceeded the maximum bacterial estimate of 500,000 per ml...

20 CFR 404.1012 - Work excluded from employment.

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2010-04-01

... 20 Employees' Benefits 2 2010-04-01 2010-04-01 false Work excluded from employment. 404.1012... DISABILITY INSURANCE (1950- ) Employment, Wages, Self-Employment, and Self-Employment Income Work Excluded from Employment § 404.1012 Work excluded from employment. Certain kinds of work performed by an...

Can we identify non-stationary dynamics of trial-to-trial variability?

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Emili Balaguer-Ballester

Full Text Available Identifying sources of the apparent variability in non-stationary scenarios is a fundamental problem in many biological data analysis settings. For instance, neurophysiological responses to the same task often vary from each repetition of the same experiment (trial to the next. The origin and functional role of this observed variability is one of the fundamental questions in neuroscience. The nature of such trial-to-trial dynamics however remains largely elusive to current data analysis approaches. A range of strategies have been proposed in modalities such as electro-encephalography but gaining a fundamental insight into latent sources of trial-to-trial variability in neural recordings is still a major challenge. In this paper, we present a proof-of-concept study to the analysis of trial-to-trial variability dynamics founded on non-autonomous dynamical systems. At this initial stage, we evaluate the capacity of a simple statistic based on the behaviour of trajectories in classification settings, the trajectory coherence, in order to identify trial-to-trial dynamics. First, we derive the conditions leading to observable changes in datasets generated by a compact dynamical system (the Duffing equation. This canonical system plays the role of a ubiquitous model of non-stationary supervised classification problems. Second, we estimate the coherence of class-trajectories in empirically reconstructed space of system states. We show how this analysis can discern variations attributable to non-autonomous deterministic processes from stochastic fluctuations. The analyses are benchmarked using simulated and two different real datasets which have been shown to exhibit attractor dynamics. As an illustrative example, we focused on the analysis of the rat's frontal cortex ensemble dynamics during a decision-making task. Results suggest that, in line with recent hypotheses, rather than internal noise, it is the deterministic trend which most likely underlies

31 CFR 19.950 - Excluded Parties List System

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2010-07-01

... 31 Money and Finance: Treasury 1 2010-07-01 2010-07-01 false Excluded Parties List System 19.950 Section 19.950 Money and Finance: Treasury Office of the Secretary of the Treasury GOVERNMENTWIDE DEBARMENT AND SUSPENSION (NONPROCUREMENT) Definitions § 19.950 Excluded Parties List System Excluded Parties...

Non-specific filtering of beta-distributed data.

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Wang, Xinhui; Laird, Peter W; Hinoue, Toshinori; Groshen, Susan; Siegmund, Kimberly D

2014-06-19

Non-specific feature selection is a dimension reduction procedure performed prior to cluster analysis of high dimensional molecular data. Not all measured features are expected to show biological variation, so only the most varying are selected for analysis. In DNA methylation studies, DNA methylation is measured as a proportion, bounded between 0 and 1, with variance a function of the mean. Filtering on standard deviation biases the selection of probes to those with mean values near 0.5. We explore the effect this has on clustering, and develop alternate filter methods that utilize a variance stabilizing transformation for Beta distributed data and do not share this bias. We compared results for 11 different non-specific filters on eight Infinium HumanMethylation data sets, selected to span a variety of biological conditions. We found that for data sets having a small fraction of samples showing abnormal methylation of a subset of normally unmethylated CpGs, a characteristic of the CpG island methylator phenotype in cancer, a novel filter statistic that utilized a variance-stabilizing transformation for Beta distributed data outperformed the common filter of using standard deviation of the DNA methylation proportion, or its log-transformed M-value, in its ability to detect the cancer subtype in a cluster analysis. However, the standard deviation filter always performed among the best for distinguishing subgroups of normal tissue. The novel filter and standard deviation filter tended to favour features in different genome contexts; for the same data set, the novel filter always selected more features from CpG island promoters and the standard deviation filter always selected more features from non-CpG island intergenic regions. Interestingly, despite selecting largely non-overlapping sets of features, the two filters did find sample subsets that overlapped for some real data sets. We found two different filter statistics that tended to prioritize features with

Interpretation of non-Markovian stochastic Schroedinger equations as a hidden-variable theory

International Nuclear Information System (INIS)

Gambetta, Jay; Wiseman, H.M.

2003-01-01

Do diffusive non-Markovian stochastic Schroedinger equations (SSEs) for open quantum systems have a physical interpretation? In a recent paper [Phys. Rev. A 66, 012108 (2002)] we investigated this question using the orthodox interpretation of quantum mechanics. We found that the solution of a non-Markovian SSE represents the state the system would be in at that time if a measurement was performed on the environment at that time, and yielded a particular result. However, the linking of solutions at different times to make a trajectory is, we concluded, a fiction. In this paper we investigate this question using the modal (hidden variable) interpretation of quantum mechanics. We find that the noise function z(t) appearing in the non-Markovian SSE can be interpreted as a hidden variable for the environment. That is, some chosen property (beable) of the environment has a definite value z(t) even in the absence of measurement on the environment. The non-Markovian SSE gives the evolution of the state of the system 'conditioned' on this environment hidden variable. We present the theory for diffusive non-Markovian SSEs that have as their Markovian limit SSEs corresponding to homodyne and heterodyne detection, as well as one which has no Markovian limit

Gene expression profiling of chicken cecal tonsils and ileum following oral exposure to soluble and PLGA-encapsulated CpG ODN, and lysate of Campylobacter jejuni.

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Taha-Abdelaziz, Khaled; Alkie, Tamiru Negash; Hodgins, Douglas C; Yitbarek, Alexander; Shojadoost, Bahram; Sharif, Shayan

2017-12-01

Campylobacter jejuni (C. jejuni) is a leading bacterial cause of food-borne illness in humans. Contaminated chicken meat is an important source of infection for humans. Chickens are not clinically affected by colonization, and immune responses following natural infection have limited effects on bacterial load in the gut. Induction of intestinal immune responses may possibly lead to a breakdown of the commensal relationship of chickens with Campylobacter. We have recently shown that soluble and poly D, L-lactic-co-glycolic acid (PLGA)-encapsulated CpG oligodeoxynucleotide (ODN) as well as C. jejuni lysate, are effective in reducing the intestinal burden of C. jejuni in chickens; however, the mechanisms behind this protection have yet to be determined. The present study was undertaken to investigate the mechanisms of host responses conferred by these treatments. Chickens were treated orally with soluble CpG ODN, or PLGA-encapsulated CpG ODN, or C. jejuni lysate, and expression of cytokines and antimicrobial peptides was evaluated in cecal tonsils and ileum using quantitative RT-PCR. Oral administration of soluble CpG ODN upregulated the expression of interferon (IFN)-γ, interleukin (IL)-1β, CXCLi2, transforming growth factor (TGF)-β4/1, IL-10 and IL-13, while treatment with PLGA-encapsulated CpG ODN upregulated the expression of IL-1β, CXCLi2, TGF-β4/1, IL-13, avian β-defensin (AvBD) 1, AvBD2 and cathelicidin 3 (CATHL-3). C. jejuni lysate upregulated the expression of IFN-γ, IL-1β, TGF-β4/1, IL-13, AvBD1, and CATHL-3. In conclusion, induction of cytokine and antimicrobial peptides expression in intestinal microenvironments may provide a means of reducing C. jejuni colonization in broiler chickens, a key step in reducing the incidence of campylobacteriosis in humans. Copyright © 2017 Elsevier B.V. All rights reserved.

8 CFR 1241.20 - Aliens ordered excluded.

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2010-01-01

... 8 Aliens and Nationality 1 2010-01-01 2010-01-01 false Aliens ordered excluded. 1241.20 Section 1241.20 Aliens and Nationality EXECUTIVE OFFICE FOR IMMIGRATION REVIEW, DEPARTMENT OF JUSTICE IMMIGRATION REGULATIONS APPREHENSION AND DETENTION OF ALIENS ORDERED REMOVED Deportation of Excluded Aliens...

Non-Noether Conserved Quantity for Relativistic Nonholonomic System with Variable Mass

International Nuclear Information System (INIS)

Qiao Yongfen; Li Renjie; Ma Yongsheng

2005-01-01

Using form invariance under special infinitesimal transformations in which time is not variable, the non-Noether conserved quantity of the relativistic nonholonomic system with variable mass is studied. The differential equations of motion of the system are established. The definition and criterion of the form invariance of the system under infinitesimal transformations are studied. The necessary and sufficient condition under which the form invariance is a Lie symmetry is given. The condition under which the form invariance can be led to a non-Noether conserved quantity and the form of the conserved quantity are obtained. Finally, an example is given to illustrate the application of the result.

Frequency Modulation and Spatiotemporal Stability of the sCPG in Preterm Infants with RDS

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Steven M. Barlow

2012-01-01

Full Text Available The nonnutritive suck (NNS is an observable and accessible motor behavior which is often used to make inference about brain development and pre-feeding skill in preterm and term infants. The purpose of this study was to model NNS burst compression pressure dynamics in the frequency and time domain among two groups of preterm infants, including those with respiratory distress syndrome (RDS, N=15 and 17 healthy controls. Digitized samples of NNS compression pressure waveforms recorded at a 1-week interval were collected 15 minutes prior to a scheduled feed. Regression analysis and ANOVA revealed that healthy preterm infants produced longer NNS bursts and the mean burst initiation cycle frequencies were higher when compared to the RDS group. Moreover, the initial 5 cycles of the NNS burst manifest a frequency modulated (FM segment which is a significant feature of the suck central pattern generator (sCPG, and differentially expressed in healthy and RDS infants. The NNS burst structure revealed significantly lower spatiotemporal index values for control versus RDS preterm infants during FM, and provides additional information on the microstructure of the sCPG which may be used to gauge the developmental status and progression of oromotor control systems among these fragile infants.

One negative polysomnogram does not exclude obstructive sleep apnea.

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Meyer, T J; Eveloff, S E; Kline, L R; Millman, R P

1993-03-01

Night-to-night variability of apneas on overnight polymnography exists in patients with documented obstructive sleep apnea (OSA). In this study, we evaluated the possibility that this variability may be severe enough to miss the diagnosis of OSA in patients clinically at risk for the disease. We prospectively studied 11 patients who were deemed on clinical grounds to have probable OSA, but had a negative result on overnight polysomnography. Six of the 11 patients were found to have a positive second study with a significant rise in the apnea/hypopnea index (AHI) from 3.1 +/- 1.0 to 19.8 +/- 4.7 (mean +/- SEM, p cause of the negative first study in these patients is unclear, but it does not seem related to risk factor pattern, sleep architecture, or test interval. The change in AHI was not found to be rapid eye movement (REM)-dependent. This study demonstrates that a negative first-night study is insufficient to exclude OSA in patients with one or more clinical markers of the disease.

Detection and discrimination of maintenance and de novo CpG methylation events using MethylBreak.

Science.gov (United States)

Hsu, William; Mercado, Augustus T; Hsiao, George; Yeh, Jui-Ming; Chen, Chung-Yung

2017-05-15

Understanding the principles governing the establishment and maintenance activities of DNA methyltransferases (DNMTs) can help in the development of predictive biomarkers associated with genetic disorders and diseases. A detection system was developed that distinguishes and quantifies methylation events using methylation-sensitive endonucleases and molecular beacon technology. MethylBreak (MB) is a 22-mer oligonucleotide with one hemimethylated and two unmethylated CpG sites, which are also recognition sites for Sau96I and SacII, and is attached to a fluorophore and a quencher. Maintenance methylation was quantified by fluorescence emission due to the digestion of SacII when the hemimethylated CpG site is methylated, which inhibits Sau96I cleavage. The signal difference between SacII digestion of both MB substrate and maintenance methylated MB corresponds to de novo methylation event. Our technology successfully discriminated and measured both methylation activities at different concentrations of MB and achieved a high correlation coefficient of R 2 =0.997. Additionally, MB was effectively applied to normal and cancer cell lines and in the analysis of enzymatic kinetics and RNA inhibition of recombinant human DNMT1. Copyright © 2017 Elsevier B.V. All rights reserved.

CPG-Based Locomotion Control of a Robotic Fish : Using Linear Oscillators and Reducing Control Parameters via PSO

NARCIS (Netherlands)

Wang, Chen; Xie, G.; Wang, L.; Cao, M.

The aim of the present study is to investigate the locomotion control of a robotic fish. To achieve this goal, we design a control architecture based on a novel central pattern generator (CPG) and implement it as a system of coupled linear oscillators. This design differs significantly from the

Protection of Mice from Lethal Vaccinia Virus Infection by Vaccinia Virus Protein Subunits with a CpG Adjuvant

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Sarah Reeman

2017-12-01

Full Text Available Smallpox vaccination carries a high risk of adverse events in recipients with a variety of contra-indications for live vaccines. Although alternative non-replicating vaccines have been described in the form of replication-deficient vaccine viruses, DNA vaccines, and subunit vaccines, these are less efficacious than replicating vaccines in animal models. DNA and subunit vaccines in particular have not been shown to give equivalent protection to the traditional replicating smallpox vaccine. We show here that combinations of the orthopoxvirus A27, A33, B5 and L1 proteins give differing levels of protection when administered in different combinations with different adjuvants. In particular, the combination of B5 and A27 proteins adjuvanted with CpG oligodeoxynucleotides (ODN gives a level of protection in mice that is equivalent to the Lister traditional vaccine in a lethal vaccinia virus challenge model.

Habitat assessment of non-wadeable rivers in Michigan.

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Wilhelm, Jennifer G O; Allan, J David; Wessell, Kelly J; Merritt, Richard W; Cummins, Kenneth W

2005-10-01

Habitat evaluation of wadeable streams based on accepted protocols provides a rapid and widely used adjunct to biological assessment. However, little effort has been devoted to habitat evaluation in non-wadeable rivers, where it is likely that protocols will differ and field logistics will be more challenging. We developed and tested a non-wadeable habitat index (NWHI) for rivers of Michigan, where non-wadeable rivers were defined as those of order >or=5, drainage area >or=1600 km2, mainstem lengths >or=100 km, and mean annual discharge >or=15 m3/s. This identified 22 candidate rivers that ranged in length from 103 to 825 km and in drainage area from 1620 to 16,860 km2. We measured 171 individual habitat variables over 2-km reaches at 35 locations on 14 rivers during 2000-2002, where mean wetted width was found to range from 32 to 185 m and mean thalweg depth from 0.8 to 8.3 m. We used correlation and principal components analysis to reduce the number of variables, and examined the spatial pattern of retained variables to exclude any that appeared to reflect spatial location rather than reach condition, resulting in 12 variables to be considered in the habitat index. The proposed NWHI included seven variables: riparian width, large woody debris, aquatic vegetation, bottom deposition, bank stability, thalweg substrate, and off-channel habitat. These variables were included because of their statistical association with independently derived measures of human disturbance in the riparian zone and the catchment, and because they are considered important in other habitat protocols or to the ecology of large rivers. Five variables were excluded because they were primarily related to river size rather than anthropogenic disturbance. This index correlated strongly with indices of disturbance based on the riparian (adjusted R2 = 0.62) and the catchment (adjusted R2 = 0.50), and distinguished the 35 river reaches into the categories of poor (2), fair (19), good (13), and

CpG island methylator phenotype and its association with malignancy in sporadic duodenal adenomas.

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Sun, Lifeng; Guzzetta, Angela A; Fu, Tao; Chen, Jinming; Jeschke, Jana; Kwak, Ruby; Vatapalli, Rajita; Baylin, Stephen B; Iacobuzio-Donahue, Christine A; Wolfgang, Christopher L; Ahuja, Nita

2014-05-01

CpG island methylator phenotype (CIMP) has been found in multiple precancerous and cancerous lesions, including colorectal adenomas, colorectal cancers, and duodenal adenocarcinomas. There are no reports in the literature of a relationship between CIMP status and clinicopathologic features of sporadic duodenal adenomas. This study sought to elucidate the role of methylation in duodenal adenomas and correlate it with KRAS and BRAF mutations. CIMP+ (with more than 2 markers methylated) was seen in 33.3% of duodenal adenomas; 61% of these CIMP+ adenomas were CIMP-high (with more than 3 markers methylated). Furthermore, CIMP+ status significantly correlated with older age of patients, larger size and villous type of tumor, coexistent dysplasia and periampullary location. MLH1 methylation was seen in 11.1% of duodenal adenomas and was significantly associated with CIMP+ tumors, while p16 methylation was an infrequent event. KRAS mutations were frequent and seen in 26.3% of adenomas; however, no BRAF mutations were detected. Furthermore, CIMP-high status was associated with larger size and villous type of tumor and race (non-white). These results suggest that CIMP+ duodenal adenomas may have a higher risk for developing malignancy and may require more aggressive management and surveillance.

EG-09EPIGENETIC PROFILING REVEALS A CpG HYPERMETHYLATION PHENOTYPE (CIMP) ASSOCIATED WITH WORSE PROGRESSION-FREE SURVIVAL IN MENINGIOMA

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Olar, Adriana; Wani, Khalida; Mansouri, Alireza; Zadeh, Gelareh; Wilson, Charmaine; DeMonte, Franco; Fuller, Gregory; Jones, David; Pfister, Stefan; von Deimling, Andreas; Sulman, Erik; Aldape, Kenneth

2014-01-01

BACKGROUND: Methylation profiling of solid tumors has revealed biologic subtypes, often with clinical implications. Methylation profiles of meningioma and their clinical implications are not well understood. METHODS: Ninety-two meningioma samples (n = 44 test set and n = 48 validation set) were profiled using the Illumina HumanMethylation450 BeadChip. Unsupervised clustering and analyses for recurrence-free survival (RFS) were performed. RESULTS: Unsupervised clustering of the test set using approximately 900 highly variable markers identified two clearly defined methylation subgroups. One of the groups (n = 19) showed global hypermethylation of a set of markers, analogous to CpG island methylator phenotype (CIMP). These findings were reproducible in the validation set, with 18/48 samples showing the CIMP-positive phenotype. Importantly, of 347 highly variable markers common to both the test and validation set analyses, 107 defined CIMP in the test set and 94 defined CIMP in the validation set, with an overlap of 83 markers between the two datasets. This number is much greater than expected by chance indicating reproducibly of the hypermethylated markers that define CIMP in meningioma. With respect to clinical correlation, the 37 CIMP-positive cases displayed significantly shorter RFS compared to the 55 non-CIMP cases (hazard ratio 2.9, p = 0.013). In an effort to develop a preliminary outcome predictor, a 155-marker subset correlated with RFS was identified in the test dataset. When interrogated in the validation dataset, this 155-marker subset showed a statistical trend (p < 0.1) towards distinguishing survival groups. CONCLUSIONS: This study defines the existence of a CIMP phenotype in meningioma, which involves a substantial proportion (37/92, 40%) of samples with clinical implications. Ongoing work will expand this cohort and examine identification of additional biologic differences (mutational and DNA copy number analysis) to further characterize the aberrant

Non-CpG island promoter hypomethylation and miR-149 regulate the expression of SRPX2 in colorectal cancer

DEFF Research Database (Denmark)

Oster, Bodil; Linnet, Lene; Christensen, Lise Lotte

2012-01-01

Gene silencing by DNA hypermethylation of CpG islands is a well-characterized phenomenon in cancer. The effect of hypomethylation in particular of non-CpG island genes is much less well described. By genome-wide screening, we identified 105 genes in microsatellite stable (MSS) colorectal adenocar......Gene silencing by DNA hypermethylation of CpG islands is a well-characterized phenomenon in cancer. The effect of hypomethylation in particular of non-CpG island genes is much less well described. By genome-wide screening, we identified 105 genes in microsatellite stable (MSS) colorectal...... of non-CpG island-associated promoters deregulate gene expression nearly as frequent as do CpG-island hypermethylation. The hypomethylation of SRPX2 is focal and not part of a large block. Furthermore, it often translates to an increased expression level, which may be modulated by miR-149....

Price variability and marketing method in non-ferrous metals: Slade's analysis revisited

NARCIS (Netherlands)

Gilbert, C.L.; Ferretti, F.

2002-01-01

We examine the impact of the pricing regime on price variability with reference to the non-ferrous metals industry. Theoretical arguments are ambiguous, but suggest that the extent of monopoly power is more important than the pricing regime as a determinant of variability. Slade (Quart. J. Econ. 106

Excluded from social security: rejections of disability pension applications in Norway 1998-2004.

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Galaasen, Anders Mølster; Bruusgaard, Dag; Claussen, Bjørgulf

2012-03-01

Admission to disability pension (DP) in Norway, like most other countries, requires a medical condition as the main cause of income reduction. Still, a widespread assumption is that much of the recruitment to the programme is rather due to non-medical, mainly labour market factors. In this article, we study the grey zones between acceptance and rejection of DP applications, in light of the concept of marginalisation. From the total Norwegian population, aged 18-66 in 1998, we included all first-time applications for DP between 1998 and 2004. Logistic regressions of both application and application outcome were then performed, controlling for a range of socioeconomic variables and medical diagnosis. Medical diagnosis had the strongest impact on application outcome, together with the applicant's age. High rejection risk was found among applicants with complex musculoskeletal diagnoses, and also for complex psychiatric diagnoses as compared to well-defined ones. Persons having previously received social assistance more often applied for a DP and more often were rejected. The same is true, though on a lesser scale, for people with a weak affiliation to the labour market. The DP programme in Norway is to a large degree medically oriented, not only judicially but also in practice. Nevertheless, non-medical factors have a bearing on both application rates and application outcome. The control system seems to work in a way that excludes the most marginalised applicants, thus possibly contributing to further marginalisation of already disadvantaged groups.

Continuous-variable entanglement distillation of non-Gaussian mixed states

International Nuclear Information System (INIS)

Dong Ruifang; Lassen, Mikael; Heersink, Joel; Marquardt, Christoph; Leuchs, Gerd; Filip, Radim; Andersen, Ulrik L.

2010-01-01

Many different quantum-information communication protocols such as teleportation, dense coding, and entanglement-based quantum key distribution are based on the faithful transmission of entanglement between distant location in an optical network. The distribution of entanglement in such a network is, however, hampered by loss and noise that is inherent in all practical quantum channels. Thus, to enable faithful transmission one must resort to the protocol of entanglement distillation. In this paper we present a detailed theoretical analysis and an experimental realization of continuous variable entanglement distillation in a channel that is inflicted by different kinds of non-Gaussian noise. The continuous variable entangled states are generated by exploiting the third order nonlinearity in optical fibers, and the states are sent through a free-space laboratory channel in which the losses are altered to simulate a free-space atmospheric channel with varying losses. We use linear optical components, homodyne measurements, and classical communication to distill the entanglement, and we find that by using this method the entanglement can be probabilistically increased for some specific non-Gaussian noise channels.

29 CFR 778.225 - Talent fees excludable under regulations.

Science.gov (United States)

2010-07-01

... 29 Labor 3 2010-07-01 2010-07-01 false Talent fees excludable under regulations. 778.225 Section... Payments That May Be Excluded From the âRegular Rateâ Talent Fees in the Radio and Television Industry § 778.225 Talent fees excludable under regulations. Section 7(e)(3) provides for the exclusion from the...

Influences of excluded volume of molecules on signaling processes on the biomembrane.

Directory of Open Access Journals (Sweden)

Masashi Fujii

Full Text Available We investigate the influences of the excluded volume of molecules on biochemical reaction processes on 2-dimensional surfaces using a model of signal transduction processes on biomembranes. We perform simulations of the 2-dimensional cell-based model, which describes the reactions and diffusion of the receptors, signaling proteins, target proteins, and crowders on the cell membrane. The signaling proteins are activated by receptors, and these activated signaling proteins activate target proteins that bind autonomously from the cytoplasm to the membrane, and unbind from the membrane if activated. If the target proteins bind frequently, the volume fraction of molecules on the membrane becomes so large that the excluded volume of the molecules for the reaction and diffusion dynamics cannot be negligible. We find that such excluded volume effects of the molecules induce non-trivial variations of the signal flow, defined as the activation frequency of target proteins, as follows. With an increase in the binding rate of target proteins, the signal flow varies by i monotonically increasing; ii increasing then decreasing in a bell-shaped curve; or iii increasing, decreasing, then increasing in an S-shaped curve. We further demonstrate that the excluded volume of molecules influences the hierarchical molecular distributions throughout the reaction processes. In particular, when the system exhibits a large signal flow, the signaling proteins tend to surround the receptors to form receptor-signaling protein clusters, and the target proteins tend to become distributed around such clusters. To explain these phenomena, we analyze the stochastic model of the local motions of molecules around the receptor.

Inhibitory effects of unmethylated CpG oligodeoxynucleotides on MHC class I-deficient and -proficient HPV16-associated tumours

Czech Academy of Sciences Publication Activity Database

Reiniš, Milan; Šímová, Jana; Bubeník, Jan

2006-01-01

Roč. 118, č. 7 (2006), s. 1836-1842 ISSN 0020-7136 R&D Projects: GA ČR(CZ) GA301/04/0492 Institutional research plan: CEZ:AV0Z50520514 Keywords : HPV16 * immunotherapy * CpG oligodeoxynucleotides Subject RIV: EC - Immunology Impact factor: 4.693, year: 2006

Fluctuation relations with intermittent non-Gaussian variables.

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Budini, Adrián A

2011-12-01

Nonequilibrium stationary fluctuations may exhibit a special symmetry called fluctuation relations (FRs). Here, we show that this property is always satisfied by the subtraction of two random and independent variables related by a thermodynamiclike change of measure. Taking one of them as a modulated Poisson process, it is demonstrated that intermittence and FRs are compatible properties that may coexist naturally. Strong non-Gaussian features characterize the probability distribution and its generating function. Their associated large deviation functions develop a "kink" at the origin and a plateau regime respectively. Application of this model in different stationary nonequilibrium situations is discussed.

The potential of immunostimulatory CpG DNA for inducing immunity against genital herpes: opportunities and challenges.

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Harandi, Ali M

2004-07-01

Herpes simplex virus type 2 (HSV-2) invades human genital tract mucosa and following local replications can be rapidly transmitted via peripheral nerve axons to the sacral ganglia where it can establish latency. Reactivation of the latent viral reservoir results in recurrent ulcers in the genital region. Innate immunity, the first line of defence during both primary and recurrent genital herpes infections, is crucial during the period of acute infection to limit early virus replication and to facilitate the development of an appropriate specific acquired immunity. Recent developments in immunology reveal that the mammalian innate immune systems use Toll-like receptor (TLR) to specifically sense evolutionary conserved molecules such as bacterial DNA in pathogens. Recently, local-vaginal delivery of CpG containing oligodeoxynucleotide (ODN), a synthetic mimic of bacterial DNA, holds substantial promise as a strong inducer of innate immunity against genital herpes infections in the animal models of the disease. These preclinical observations provide a scientific ground work for introduction of this novel intervention strategy to clinic. This review aims to highlight recent developments and future challenges in use of immunostimulatory CpG ODN for inducing immunity against genital herpes infection and disease.

CpG island methylator phenotype in adenocarcinomas from the digestive tract: Methods, conclusions, and controversies

Science.gov (United States)

Sánchez-Vega, Francisco; Gotea, Valer; Chen, Yun-Ching; Elnitski, Laura

2017-01-01

Over the last two decades, cancer-related alterations in DNA methylation that regulate transcription have been reported for a variety of tumors of the gastrointestinal tract. Due to its relevance for translational research, great emphasis has been placed on the analysis and molecular characterization of the CpG island methylator phenotype (CIMP), defined as widespread hypermethylation of CpG islands in clinically distinct subsets of cancer patients. Here, we present an overview of previous work in this field and also explore some open questions using cross-platform data for esophageal, gastric, and colorectal adenocarcinomas from The Cancer Genome Atlas. We provide a data-driven, pan-gastrointestinal stratification of individual samples based on CIMP status and we investigate correlations with oncogenic alterations, including somatic mutations and epigenetic silencing of tumor suppressor genes. Besides known events in CIMP such as BRAF V600E mutation, CDKN2A silencing or MLH1 inactivation, we discuss the potential role of emerging actors such as Wnt pathway deregulation through truncating mutations in RNF43 and epigenetic silencing of WIF1. Our results highlight the existence of molecular similarities that are superimposed over a larger backbone of tissue-specific features and can be exploited to reduce heterogeneity of response in clinical trials. PMID:28344746

Non-parametric tests of productive efficiency with errors-in-variables

NARCIS (Netherlands)

Kuosmanen, T.K.; Post, T.; Scholtes, S.

2007-01-01

We develop a non-parametric test of productive efficiency that accounts for errors-in-variables, following the approach of Varian. [1985. Nonparametric analysis of optimizing behavior with measurement error. Journal of Econometrics 30(1/2), 445-458]. The test is based on the general Pareto-Koopmans

Demethylation by 5-aza-2'-deoxycytidine in colorectal cancer cells targets genomic DNA whilst promoter CpG island methylation persists

International Nuclear Information System (INIS)

Mossman, David; Kim, Kyu-Tae; Scott, Rodney J

2010-01-01

DNA methylation and histone acetylation are epigenetic modifications that act as regulators of gene expression. Aberrant epigenetic gene silencing in tumours is a frequent event, yet the factors which dictate which genes are targeted for inactivation are unknown. DNA methylation and histone acetylation can be modified with the chemical agents 5-aza-2'-deoxycytidine (5-aza-dC) and Trichostatin A (TSA) respectively. The aim of this study was to analyse de-methylation and re-methylation and its affect on gene expression in colorectal cancer cell lines treated with 5-aza-dC alone and in combination with TSA. We also sought to identify methylation patterns associated with long term reactivation of previously silenced genes. Colorectal cancer cell lines were treated with 5-aza-dC, with and without TSA, to analyse global methylation decreases by High Performance Liquid Chromatography (HPLC). Re-methylation was observed with removal of drug treatments. Expression arrays identified silenced genes with differing patterns of expression after treatment, such as short term reactivation or long term reactivation. Sodium bisulfite sequencing was performed on the CpG island associated with these genes and expression was verified with real time PCR. Treatment with 5-aza-dC was found to affect genomic methylation and to a lesser extent gene specific methylation. Reactivated genes which remained expressed 10 days post 5-aza-dC treatment featured hypomethylated CpG sites adjacent to the transcription start site (TSS). In contrast, genes with uniformly hypermethylated CpG islands were only temporarily reactivated. These results imply that 5-aza-dC induces strong de-methylation of the genome and initiates reactivation of transcriptionally inactive genes, but this does not require gene associated CpG island de-methylation to occur. In addition, for three of our selected genes, hypomethylation at the TSS of an epigenetically silenced gene is associated with the long term reversion of

Correlation of pathologic features with CpG island methylator phenotype (CIMP) by quantitative DNA methylation analysis in colorectal carcinoma.

Science.gov (United States)

Ogino, Shuji; Odze, Robert D; Kawasaki, Takako; Brahmandam, Mohan; Kirkner, Gregory J; Laird, Peter W; Loda, Massimo; Fuchs, Charles S

2006-09-01

Extensive gene promoter methylation in colorectal carcinoma has been termed the CpG island methylator phenotype (CIMP). Previous studies on CIMP used primarily methylation-specific polymerase chain reaction (PCR), which, unfortunately, may detect low levels of methylation that has little or no biological significance. Utilizing quantitative real-time PCR (MethyLight), we measured DNA methylation in a panel of 5 CIMP-specific gene promoters (CACNA1G, CDKN2A (p16), CRABP1, MLH1, and NEUROG1) in 459 colorectal carcinomas obtained from 2 large prospective cohort studies. CIMP was defined as tumors that showed methylation in >or=4/5 promoters. CIMP was significantly associated with the presence of mucinous or signet ring cell morphology, marked Crohn's-like lymphoid reaction, tumor infiltrating lymphocytes, marked peritumoral lymphocytic reaction, tumor necrosis, tumor cell sheeting, and poor differentiation. All these features have previously been associated with microsatellite instability (MSI). Therefore, we divided the 459 colorectal carcinomas into 6 subtypes, namely, MSI-high (MSI-H)/CIMP, MSI-H/non-CIMP, MSI-low (MSI-L)/CIMP, MSI-L/non-CIMP, microsatellite stable/CIMP, and micro satellite sstable/non-CIMP. Compared with MSI-H/non-CIMP, MSI-H/CIMP was associated with marked tumor infiltrating lymphocytes, tumor necrosis, sheeting, and poor differentiation (all PCIMP, MSI-L/CIMP was associated with tumors that had CIMP. Both MSI and CIMP appear to play a role in the pathogenesis of specific morphologic patterns of colorectal carcinoma.

Radiolabelling of glycosylated MFE-23::CPG2 fusion protein (MFECP1) with 99mTc for quantitation of tumour antibody-enzyme localisation in antibody-directed enzyme pro-drug therapy (ADEPT).

Science.gov (United States)

Francis, R J; Mather, S J; Chester, K; Sharma, S K; Bhatia, J; Pedley, R B; Waibel, R; Green, A J; Begent, R H J

2004-08-01

MFECP1 is a glycosylated recombinant fusion protein composed of MFE-23, a high-affinity anti-carcinoembryonic antigen (CEA) single chain Fv (scFv), fused to the enzyme carboxypeptidase G2 (CPG2), and has been constructed for use in antibody-directed enzyme pro-drug therapy (ADEPT). Radiolabelling of glycosylated MFECP1 with technetium-99m was developed for the purpose of determining tumour localisation of MFECP1 in a phase I ADEPT clinical study. The method used was 99mTc-carbonyl [99mTc(H2O)3(CO)3]+ (abbreviated to TcCO) mediated labelling of 99mTc to the hexahistidine (His) tag of MFECP1. MFECP1 fusion protein was labelled with TcCO under a variety of conditions, and this was shown to be a relatively simple and robust method. Tissue biodistribution was assessed in a CEA-expressing LS174T (human colon carcinoma) nude mouse xenograft model. Tissues were taken at 1, 4 and 6 h for assessment of distribution of radioactivity and for measurement of CPG2 enzyme levels. The amount of radioactivity retained by the tumour proved to be an accurate estimation of actual measured enzyme activity, indicating that this radiolabelling method does not appear to damage the antibody-antigen binding or the enzyme activity of MFECP1. However, correlation between CPG2 enzyme activity and measured radioactivity in liver, spleen and kidney was poor, indicating retention of radioactivity in non-tumour sites but loss of enzyme activity. The high retention of technetium radioisotope in normal tissues may limit the clinical applicability of this radiolabelling method for MFECP1; however, these results suggest that this technique does have applicability for measuring the biodistribution of His-tagged recombinant proteins.

Radiolabelling of glycosylated MFE-23::CPG2 fusion protein (MFECP1) with 99mTc for quantitation of tumour antibody-enzyme localisation in antibody-directed enzyme pro-drug therapy (ADEPT)

International Nuclear Information System (INIS)

Francis, R.J.; Chester, K.; Sharma, S.K.; Bhatia, J.; Pedley, R.B.; Green, A.J.; Begent, R.H.J.; Mather, S.J.; Waibel, R.

2004-01-01

MFECP1 is a glycosylated recombinant fusion protein composed of MFE-23, a high-affinity anti-carcinoembryonic antigen (CEA) single chain Fv (scFv), fused to the enzyme carboxypeptidase G2 (CPG2), and has been constructed for use in antibody-directed enzyme pro-drug therapy (ADEPT). Radiolabelling of glycosylated MFECP1 with technetium-99m was developed for the purpose of determining tumour localisation of MFECP1 in a phase I ADEPT clinical study. The method used was 99m Tc-carbonyl [ 99m Tc(H 2 O) 3 (CO) 3 ] + (abbreviated to TcCO) mediated labelling of 99m Tc to the hexahistidine (His) tag of MFECP1. MFECP1 fusion protein was labelled with TcCO under a variety of conditions, and this was shown to be a relatively simple and robust method. Tissue biodistribution was assessed in a CEA-expressing LS174T (human colon carcinoma) nude mouse xenograft model. Tissues were taken at 1, 4 and 6 h for assessment of distribution of radioactivity and for measurement of CPG2 enzyme levels. The amount of radioactivity retained by the tumour proved to be an accurate estimation of actual measured enzyme activity, indicating that this radiolabelling method does not appear to damage the antibody-antigen binding or the enzyme activity of MFECP1. However, correlation between CPG2 enzyme activity and measured radioactivity in liver, spleen and kidney was poor, indicating retention of radioactivity in non-tumour sites but loss of enzyme activity. The high retention of technetium radioisotope in normal tissues may limit the clinical applicability of this radiolabelling method for MFECP1; however, these results suggest that this technique does have applicability for measuring the biodistribution of His-tagged recombinant proteins. (orig.)

Modulation of transcription factor binding and epigenetic regulation of the MLH1 CpG island and shore by polymorphism rs1800734 in colorectal cancer.

Science.gov (United States)

Savio, Andrea J; Bapat, Bharati

2017-06-03

The MLH1 promoter polymorphism rs1800734 is associated with MLH1 CpG island hypermethylation and expression loss in colorectal cancer (CRC). Conversely, variant rs1800734 is associated with MLH1 shore, but not island, hypomethylation in peripheral blood mononuclear cell DNA. To explore these distinct patterns, MLH1 CpG island and shore methylation was assessed in CRC cell lines stratified by rs1800734 genotype. Cell lines containing the variant A allele demonstrated MLH1 shore hypomethylation compared to wild type (GG). There was significant enrichment of transcription factor AP4 at the MLH1 promoter in GG and GA cell lines, but not the AA cell line, by chromatin immunoprecipitation studies. Preferential binding to the G allele was confirmed by sequencing in the GA cell line. The enhancer-associated histone modification H3K4me1 was enriched at the MLH1 shore; however, H3K27ac was not, indicating the shore is an inactive enhancer. These results demonstrate the role of variant rs1800734 in altering transcription factor binding as well as epigenetics at regions beyond the MLH1 CpG island in which it is located.

A Non-linear "Inflation-Relative Prices Variability" Relationship: Evidence from Latin America

OpenAIRE

Mª Ángeles Caraballo Pou; Carlos Dabús; Diego Caramuta

2006-01-01

This paper presents evidence on a non-linear "inflation-relative prices variability" relationship in three Latin American countries with very high inflation experiences: Argentina, Brazil and Peru. More precisely, and in contrast to results found in previous literature for similar countries, we find a non-concave relation at higher inflation regimes, i.e. when inflation rate surpasses certain threshold. This non-concavity is mainly explained by the unexpected component of inflation, which sug...

What is the Right to Exclude Immigrants?

DEFF Research Database (Denmark)

Lægaard, Sune

2010-01-01

It is normally taken for granted that states have a right to control immigration into their territory. When immigration is raised as a normative issue two questions become salient, one about what the right to exclude is, and one about whether and how it might be justified. This paper considers...... the first question. The paper starts by noting that standard debates about immigration have not addressed what the right to exclude is. Standard debates about immigration furthermore tend to result either in fairly strong cases for open borders or in denials that considerations of justice apply...... to immigration at all, which results in state discretion positions. This state of debate is both theoretically unsatisfactory and normatively implausible. The paper therefore explores an alternative approach to the right to exclude immigrants from the perspective of recent debates about the territorial rights...

21 CFR 1308.26 - Excluded veterinary anabolic steroid implant products.

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 9 2010-04-01 2010-04-01 false Excluded veterinary anabolic steroid implant... SCHEDULES OF CONTROLLED SUBSTANCES Excluded Veterinary Anabolic Steroid Implant Products § 1308.26 Excluded veterinary anabolic steroid implant products. (a) Products containing an anabolic steroid, that are expressly...

IGFBP3 Promoter Methylation in Colorectal Cancer: Relationship with Microsatellite Instability, CpG Island Methylator Phenotype, p53

Directory of Open Access Journals (Sweden)

Takako Kawasaki

2007-12-01

Full Text Available Insulin-like growth factor binding protein 3 (IGFBP3, which is induced by wild-type p53, regulates IGF and interacts with the TGF-β pathway. IGFBP3 promoter methylation may occur in colorectal cancer with or without the CpG island methylator phenotype (CIMP, which is associated with microsatellite instability (MSI and TGFBR2 mutation. We examined the relationship between IGFBP3 methylation, p53 expression, CIMP and MSI in 902 population-based colorectal cancers. Utilizing real-time PCR (MethyLight, we quantified promoter methylation in IGFBP3 and eight other CIMP-high-specific promoters (CACNA1G, CDKN2A, CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1. IGFBP3 methylation was far more frequent in non-MSI-high CIMP-high tumors (85% = 35/41 than in MSI-high CIMPhigh (49% = 44/90, P < .0001, MSI-high non-CIMP-high (17% = 6/36, P < .0001, non-MSI-high non-CIMP-high tumors (22% = 152/680, P < .0001. Among CIMPhigh tumors, the inverse relationship between MSI and IGFBP3 methylation persisted in p53-negative tumors (P < .0001, but not in p53-positive tumors. IGFBP3 methylation was associated inversely with TGFBR2 mutation in MSI-high non-CIMP-high tumors (P = .02. In conclusion, IGFBP3 methylation is inversely associated with MSI in CIMP-high colorectal cancers, this relationship is limited to p53-negative tumors. Our data suggest complex relationship between global genomic/epigenomic phenomena (such as MSI/ CIMP, single molecular events (e.g., IGFBP3 methylation, TP53 mutation, TGFBR2 mutation, the related pathways.

The CpG island methylator phenotype (CIMP) in colorectal cancer.

Science.gov (United States)

Nazemalhosseini Mojarad, Ehsan; Kuppen, Peter Jk; Aghdaei, Hamid Asadzadeh; Zali, Mohammad Reza

2013-01-01

It is clear that colorectal cancer (CRC) develops through multiple genetic and epigenetic pathways. These pathways may be determined on the basis of three molecular features: (i) mutations in DNA mismatch repair genes, leading to a DNA microsatellite instability (MSI) phenotype, (ii) mutations in APC and other genes that activate Wnt pathway, characterized by chromosomal instability (CIN) phenotype, and (iii) global genome hypermethylation, resulting in switch off of tumor suppressor genes, indicated as CpG island methylator phenotype (CIMP). Each of these pathways is characterized by specific pathological features, mechanisms of carcinogenesis and process of tumor development. The molecular aspects of these pathways have been used clinically in the diagnosis, screening and management of patients with colorectal cancer. In this review we especially describe various aspects of CIMP, one of the important and rather recently discovered pathways that lead to colorectal cancer.

Realistic continuous-variable quantum teleportation with non-Gaussian resources

International Nuclear Information System (INIS)

Dell'Anno, F.; De Siena, S.; Illuminati, F.

2010-01-01

We present a comprehensive investigation of nonideal continuous-variable quantum teleportation implemented with entangled non-Gaussian resources. We discuss in a unified framework the main decoherence mechanisms, including imperfect Bell measurements and propagation of optical fields in lossy fibers, applying the formalism of the characteristic function. By exploiting appropriate displacement strategies, we compute analytically the success probability of teleportation for input coherent states and two classes of non-Gaussian entangled resources: two-mode squeezed Bell-like states (that include as particular cases photon-added and photon-subtracted de-Gaussified states), and two-mode squeezed catlike states. We discuss the optimization procedure on the free parameters of the non-Gaussian resources at fixed values of the squeezing and of the experimental quantities determining the inefficiencies of the nonideal protocol. It is found that non-Gaussian resources enhance significantly the efficiency of teleportation and are more robust against decoherence than the corresponding Gaussian ones. Partial information on the alphabet of input states allows further significant improvement in the performance of the nonideal teleportation protocol.

The Effect of Financial and Non-Financial Variables to Firm Performance: Comparison Between Indonesia and Thailand

Directory of Open Access Journals (Sweden)

Hasni Yusrianti

2016-04-01

Full Text Available The purpose of this research is to test the effect of financial and non-financial variables to firm performances between Indonesia and Thailand. The observation data used in this study is manufacturing companies from several sectors.  Secondary data was used, collected from Indonesia Stock Exchange and Stock Exchange of Thailand during 2011 - 2013. By combining 3 years research, there are 55 Indonesian companies and 50 Thailand companies that meet predetermined criteria.  Multiple Regression was used to analyze. This study uses Return on Equity, Earnings per Share, Market Value Added as financial variables and Earnings Quality, Institutional Ownership, Independent Commissioner, Audit Committee, Corporate Social Responsibility as non-financial variables. Test results show that both financial and non-financial variables can effect to firm performance.

Determining coding CpG islands by identifying regions significant for pattern statistics on Markov chains.

Science.gov (United States)

Singer, Meromit; Engström, Alexander; Schönhuth, Alexander; Pachter, Lior

2011-09-23

Recent experimental and computational work confirms that CpGs can be unmethylated inside coding exons, thereby showing that codons may be subjected to both genomic and epigenomic constraint. It is therefore of interest to identify coding CpG islands (CCGIs) that are regions inside exons enriched for CpGs. The difficulty in identifying such islands is that coding exons exhibit sequence biases determined by codon usage and constraints that must be taken into account. We present a method for finding CCGIs that showcases a novel approach we have developed for identifying regions of interest that are significant (with respect to a Markov chain) for the counts of any pattern. Our method begins with the exact computation of tail probabilities for the number of CpGs in all regions contained in coding exons, and then applies a greedy algorithm for selecting islands from among the regions. We show that the greedy algorithm provably optimizes a biologically motivated criterion for selecting islands while controlling the false discovery rate. We applied this approach to the human genome (hg18) and annotated CpG islands in coding exons. The statistical criterion we apply to evaluating islands reduces the number of false positives in existing annotations, while our approach to defining islands reveals significant numbers of undiscovered CCGIs in coding exons. Many of these appear to be examples of functional epigenetic specialization in coding exons.

CpG island protects Rous sarcoma virus-derived vectors integrated into nonpermissive cells from DNA methylation and transcriptional suppression

Czech Academy of Sciences Publication Activity Database

Hejnar, Jiří; Hájková, P.; Plachý, Jiří; Elleder, Daniel; Stepanets, Volodymyr; Svoboda, Jan

2001-01-01

Roč. 98, č. 2 (2001), s. 565-569 ISSN 0027-8424 R&D Projects: GA ČR GA312/97/P082; GA ČR GA312/98/0825 Keywords : CpG island * provirus silencing * DNA methylation Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 10.890, year: 2001

Body size, physical activity and risk of colorectal cancer with or without the CpG island methylator phenotype (CIMP)

NARCIS (Netherlands)

Hughes, L.A.E.; Simons, C.C.J.M.; Brandt, P.A. van den; Goldbohm, R.A.; Goeij, A.F. de; Bruïne, A.P. de; Engeland, M. van; Weijenberg, M.P.

2011-01-01

Background: We investigated how body size and physical activity influence the risk of the CpG island methylator phenotype (CIMP) in colorectal cancer (CRC). Methods: In the Netherlands Cohort Study (n = 120,852), risk factors were self-reported at baseline in 1986. After 7.3 years of follow-up, 603

Anxiety Associated Increased CpG Methylation in the Promoter of Asb1: A Translational Approach Evidenced by Epidemiological and Clinical Studies and a Murine Model.

Science.gov (United States)

Emeny, Rebecca T; Baumert, Jens; Zannas, Anthony S; Kunze, Sonja; Wahl, Simone; Iurato, Stella; Arloth, Janine; Erhardt, Angelika; Balsevich, Georgia; Schmidt, Mathias V; Weber, Peter; Kretschmer, Anja; Pfeiffer, Liliane; Kruse, Johannes; Strauch, Konstantin; Roden, Michael; Herder, Christian; Koenig, Wolfgang; Gieger, Christian; Waldenberger, Melanie; Peters, Annette; Binder, Elisabeth B; Ladwig, Karl-Heinz

2018-01-01

Epigenetic regulation in anxiety is suggested, but evidence from large studies is needed. We conducted an epigenome-wide association study (EWAS) on anxiety in a population-based cohort and validated our finding in a clinical cohort as well as a murine model. In the KORA cohort, participants (n=1522, age 32-72 years) were administered the Generalized Anxiety Disorder (GAD-7) instrument, whole blood DNA methylation was measured (Illumina 450K BeadChip), and circulating levels of hs-CRP and IL-18 were assessed in the association between anxiety and methylation. DNA methylation was measured using the same instrument in a study of patients with anxiety disorders recruited at the Max Planck Institute of Psychiatry (MPIP, 131 non-medicated cases and 169 controls). To expand our mechanistic understanding, these findings were reverse translated in a mouse model of acute social defeat stress. In the KORA study, participants were classified according to mild, moderate, or severe levels of anxiety (29.4%/6.0%/1.5%, respectively). Severe anxiety was associated with 48.5% increased methylation at a single CpG site (cg12701571) located in the promoter of the gene encoding Asb1 (β-coefficient=0.56 standard error (SE)=0.10, p (Bonferroni)=0.005), a protein hypothetically involved in regulation of cytokine signaling. An interaction between IL-18 and severe anxiety with methylation of this CpG cite showed a tendency towards significance in the total population (p=0.083) and a significant interaction among women (p=0.014). Methylation of the same CpG was positively associated with Panic and Agoraphobia scale (PAS) scores (β=0.005, SE=0.002, p=0.021, n=131) among cases in the MPIP study. In a murine model of acute social defeat stress, Asb1 gene expression was significantly upregulated in a tissue-specific manner (p=0.006), which correlated with upregulation of the neuroimmunomodulating cytokine interleukin 1 beta. Our findings suggest epigenetic regulation of the stress

eMethylsorb: electrochemical quantification of DNA methylation at CpG resolution using DNA-gold affinity interactions.

Science.gov (United States)

Sina, Abu Ali Ibn; Howell, Sidney; Carrascosa, Laura G; Rauf, Sakandar; Shiddiky, Muhammad J A; Trau, Matt

2014-11-07

We report a simple electrochemical method referred to as "eMethylsorb" for the detection of DNA methylation. The method relies on the base dependent affinity interaction of DNA with gold. The methylation status of DNA is quantified by monitoring the electrochemical current as a function of the relative adsorption level of bisulphite treated DNA samples onto a bare gold electrode. This method can successfully distinguish methylated and unmethylated epigenotypes at single CpG resolution.

A Study of Locale-Wise Differences in Certain Cognitive and Non-Cognitive Variables

Science.gov (United States)

Puar, Surjit Singh

2012-01-01

The present study has been designed to investigate the locale-wise differences among high school students on the basis of certain cognitive variables like general mental ability and academic achievement and non-cognitive variables such as anxiety, emotional maturity and social maturity. The study was conducted over a sample of 400 (200 boys and…

CpG Island Methylation in Colorectal Cancer: Past, Present and Future

Directory of Open Access Journals (Sweden)

Karen Curtin

2011-01-01

Full Text Available The concept of a CpG island methylator phenotype, or CIMP, quickly became the focus of several colorectal cancer studies describing its clinical and pathological features after its introduction in 1999 by Toyota and colleagues. Further characterization of CIMP in tumors lead to widespread acceptance of the concept, as expressed by Shen and Issa in their 2005 editorial, “CIMP, at last.” Since that time, extensive research efforts have brought great insights into the epidemiology and prognosis of CIMP+ tumors and other epigenetic mechanisms underlying tumorigenesis. With the advances in technology and subsequent cataloging of the human methylome in cancer and normal tissue, new directions in research to understand CIMP and its role in complex biological systems yield hope for future epigenetically based diagnostics and treatments.

Estimating structural equation models with non-normal variables by using transformations

NARCIS (Netherlands)

Montfort, van K.; Mooijaart, A.; Meijerink, F.

2009-01-01

We discuss structural equation models for non-normal variables. In this situation the maximum likelihood and the generalized least-squares estimates of the model parameters can give incorrect estimates of the standard errors and the associated goodness-of-fit chi-squared statistics. If the sample

Separation of variables in anisotropic models and non-skew-symmetric elliptic r-matrix

Science.gov (United States)

Skrypnyk, Taras

2017-05-01

We solve a problem of separation of variables for the classical integrable hamiltonian systems possessing Lax matrices satisfying linear Poisson brackets with the non-skew-symmetric, non-dynamical elliptic so(3)⊗ so(3)-valued classical r-matrix. Using the corresponding Lax matrices, we present a general form of the "separating functions" B( u) and A( u) that generate the coordinates and the momenta of separation for the associated models. We consider several examples and perform the separation of variables for the classical anisotropic Euler's top, Steklov-Lyapunov model of the motion of anisotropic rigid body in the liquid, two-spin generalized Gaudin model and "spin" generalization of Steklov-Lyapunov model.

Study on the security of discrete-variable quantum key distribution over non-Markovian channels

International Nuclear Information System (INIS)

Huang Peng; Zhu Jun; He Guangqiang; Zeng Guihua

2012-01-01

The dynamic of the secret key rate of the discrete-variable quantum key distribution (QKD) protocol over the non-Markovian quantum channel is investigated. In particular, we calculate the secret key rate for the six-state protocol over non-Markovian depolarizing channels with coloured noise and Markovian depolarizing channels with Gaussian white noise, respectively. We find that the secure secret key rate for the non-Markovian depolarizing channel will be larger than the Markovian one under the same conditions even when their upper bounds of tolerable quantum bit error rate are equal. This indicates that this coloured noise in the non-Markovian depolarizing channel can enhance the security of communication. Moreover, we show that the secret key rate fluctuates near the secure point when the coupling strength of the system with the environment is high. The results demonstrate that the non-Markovian effects of the transmission channel can have a positive impact on the security of discrete-variable QKD. (paper)

CpG oligodeoxynucleotide induces apoptosis and cell cycle arrest in A20 lymphoma cells via TLR9-mediated pathways.

Science.gov (United States)

Qi, Xu-Feng; Zheng, Li; Kim, Cheol-Su; Lee, Kyu-Jae; Kim, Dong-Heui; Cai, Dong-Qing; Qin, Jun-Wen; Yu, Yan-Hong; Wu, Zheng; Kim, Soo-Ki

2013-07-01

Recent studies have suggested that the anti-cancer activity of CpG-oligodeoxynucleotides (CpG-ODNs) is owing to their immunomodulatory effects in tumor-bearing host. The purpose of this study is to investigate the directly cytotoxic activity of KSK-CpG, a novel CpG-ODN with an alternative CpG motif, against A20 and EL4 lymphoma cells in comparison with previously used murine CpG motif (1826-CpG). To evaluate the potential cytotoxic effects of KSK-CpG on lymphoma cells, cell viability assay, confocal microscopy, flow cytometry, DNA fragmentation, Western blotting, and reverse transcription-polymerase chain reaction (RT-PCR) analysis were used. We found that KSK-CpG induced direct cytotoxicity in A20 lymphoma cells, but not in EL4 lymphoma cells, at least in part via TLR9-mediated pathways. Apoptotic cell death was demonstrated to play an important role in CpG-ODNs-induced cytotoxicity. In addition, both mitochondrial membrane potential decrease and G1-phase arrest were involved in KSK-CpG-induced apoptosis in A20 cells. The activities of apoptotic molecules such as caspase-3, PARP, and Bax were increased, but the activation of p27 Kip1 and ERK were decreased in KSK-CpG-treated A20 cells. Furthermore, autocrine IFN-γ partially contributed to apoptotic cell death in KSK-CpG-treated A20 cells. Collectively, our findings suggest that KSK-CpG induces apoptotic cell death in A20 lymphoma cells at least in part by inducing G1-phase arrest and autocrine IFN-γ via increasing TLR9 expression, without the need for immune system of tumor-bearing host. This new understanding supports the development of TLR9-targeted therapy with CpG-ODN as a direct therapeutic agent for treating B lymphoma. Copyright © 2013 Elsevier Ltd. All rights reserved.

Aberrant septin 9 DNA methylation in colorectal cancer is restricted to a single CpG island

International Nuclear Information System (INIS)

Wasserkort, Reinhold; Kalmar, Alexandra; Valcz, Gabor; Spisak, Sandor; Krispin, Manuel; Toth, Kinga; Tulassay, Zsolt; Sledziewski, Andrew Z; Molnar, Bela

2013-01-01

The septin 9 gene (SEPT9) codes for a GTP-binding protein associated with filamentous structures and cytoskeleton formation. SEPT9 plays a role in multiple cancers as either an oncogene or a tumor suppressor gene. Regulation of SEPT9 expression is complex and not well understood; however, hypermethylation of the gene was recently introduced as a biomarker for early detection of colorectal cancer (CRC) and has been linked to cancer of the breast and of the head and neck. Because the DNA methylation landscape of different regions of SEPT9 is poorly understood in cancer, we analyzed the methylation patterns of this gene in distinct cell populations from normal and diseased colon mucosa. Laser capture microdissection was performed to obtain homogeneous populations of epithelial and stromal cells from normal, adenomatous, and tumorous colon mucosa. Microdissected samples were analyzed using direct bisulfite sequencing to determine the DNA methylation status of eight regions within and near the SEPT9 gene. Septin-9 protein expression was assessed using immunohistochemistry (IHC). Regions analyzed in SEPT9 were unmethylated in normal tissue except for a methylation boundary detected downstream of the largest CpG island. In adenoma and tumor tissues, epithelial cells displayed markedly increased DNA methylation levels (>80%, p <0.0001) in only one of the CpG islands investigated. SEPT9 methylation in stromal cells increased in adenomatous and tumor tissues (≤50%, p <0.0001); however, methylation did not increase in stromal cells of normal tissue close to the tumor. IHC data indicated a significant decrease (p <0.01) in Septin-9 protein levels in epithelial cells derived from adenoma and tumor tissues; Septin-9 protein levels in stromal cells were low in all tissues. Hypermethylation of SEPT9 in adenoma and CRC specimens is confined to one of several CpG islands of this gene. Tumor-associated aberrant methylation originates in epithelial cells; stromal cells appear to

CpG Island Methylator Phenotype-High Colorectal Cancers and Their Prognostic Implications and Relationships with the Serrated Neoplasia Pathway.

Science.gov (United States)

Rhee, Ye-Young; Kim, Kyung-Ju; Kang, Gyeong Hoon

2017-01-15

The concept of a CpG island methylator phenotype (CIMP) was first introduced by Toyota and Issa to describe a subset of colorectal cancers (CRCs) with concurrent hypermethylation of multiple CpG island loci. The concept of CIMP as a molecular carcinogenesis mechanism was consolidated by the identification of the serrated neoplasia pathway, in which CIMP participates in the initiation and progression of serrated adenomas. Distinct clinicopathological and molecular features of CIMP-high (CIMP-H) CRCs have been characterized, including proximal colon location, older age of onset, female preponderance, and frequent associations of high-level microsatellite instability and BRAF mutations. CIMP-H CRCs arise in sessile or traditional serrated adenomas and thus tend to display the morphological characteristics of serrated adenomas, including epithelial serration, vesicular nuclei, and abundant cytoplasm. Both the frequent association of CIMP and poor prognosis and different responses of CRCs to adjuvant therapy depending on CIMP status indicate clinical implications. In this review, we present an overview of the literature documenting the relevant findings of CIMP-H CRCs and their relationships with the serrated neoplasia pathway.

CpG Type A Induction of an Early Protective Environment in Experimental Multiple Sclerosis

Directory of Open Access Journals (Sweden)

James Crooks

2017-01-01

Full Text Available Experimental autoimmune encephalomyelitis (EAE is an inflammatory, demyelinating disease of the CNS that mimics human multiple sclerosis (MS, and it is thought to be driven by Th1 and Th17 myelin-reactive cells. Although adaptive immunity is clearly pivotal in the pathogenesis of EAE, with an essential role of CD4+ T cells, little is known of early, innate responses in this experimental setting. CpG-rich oligodeoxynucleotides (ODNs, typically found in microbial genomes, are potent activators of TLR9 in plasmacytoid dendritic cells (pDCs. In this study, we compared the effects of two types of CpG, namely, type A and type B, on EAE. We found that treatment with CpG type A ODN (CpG-A, known to induce high amounts of IFN-α in pDCs, significantly reduced disease severity in EAE, relative to controls (12.63±1.86 versus 23.49±1.46, resp.; p=0.001. Treatment also delayed onset of neurological deficits and reduced spinal cord demyelination, while increasing the percentage of splenic regulatory (Foxp3+ CD4+ T cells. CpG-A likewise reduced the levels of IL-17 and IFN-γ in the CNS. Mechanistic insight into those events showed that CpG-A promoted a regulatory phenotype in pDCs. Moreover, adoptive transfer of pDCs isolated from CpG-A-treated mice inhibited CNS inflammation and induced disease remission in acute-phase EAE. Our data thus identify a link between TLR9 activation by specific ligands and the induction of tolerance via innate immunity mechanisms.

Different definitions of CpG island methylator phenotype and outcomes of colorectal cancer: a systematic review

OpenAIRE

Jia, Min; Gao, Xu; Zhang, Yan; Hoffmeister, Michael; Brenner, Hermann

2016-01-01

Contradictory results were reported for the prognostic role of CpG island methylator phenotype (CIMP) among colorectal cancer (CRC) patients. Differences in the definitions of CIMP were the most common explanation for these discrepancies. The aim of this systematic review was to give an overview of the published studies on CRC prognosis according to the different definitions of CIMP. A systematic literature search was performed in MEDLINE and ISI Web of Science for articles published until 3 ...

Body size, physical activity and risk of colorectal cancer with or without the CpG island methylator phenotype (CIMP.

Directory of Open Access Journals (Sweden)

Laura A E Hughes

Full Text Available BACKGROUND: We investigated how body size and physical activity influence the risk of the CpG island methylator phenotype (CIMP in colorectal cancer (CRC. METHODS: In the Netherlands Cohort Study (n = 120,852, risk factors were self-reported at baseline in 1986. After 7.3 years of follow-up, 603 cases and 4,631 sub-cohort members were available. CIMP status according to the Weisenberger markers was determined using methylation specific PCR on DNA from paraffin embedded tumor tissue. Hazard rate ratios (HR and 95% confidence intervals for CIMP (27.7% and non-CIMP (72.3% tumors were calculated according to BMI, BMI at age 20, BMI change, trouser/skirt size, height, and physical activity. RESULTS: BMI modeled per 5 kg/m(2 increase was associated with both CIMP and non-CIMP tumors, however, HRs were attenuated when additionally adjusted for trouser/skirt size. Trouser/skirt size, per 2 size increase, was associated with both tumor subtypes, even after adjustment for BMI (CIMP HR: 1.20, 95%CI: 1.01-1.43; non-CIMP HR: 1.14, 95%CI: 1.04-1.28. Height per 5 cm was associated with both tumor sub-types, but HRs were attenuated when adjusted for body weight. BMI at age 20 was positively associated with increased risk of CIMP tumors and the association was significantly less pronounced for non-CIMP tumors (P-heterogeneity = 0.01. Physical activity was inversely associated with both subtypes, but a dose-response association was observed only for non-CIMP tumors (P-trend = 0.02. CONCLUSIONS: Body size, especially central adiposity, may increase the risk of both CIMP and non-CIMP tumors. Body fat at young age may differentially influence risk. Physical activity appears to decrease the risk of CRC regardless of these molecular subtypes.

Body size, physical activity and risk of colorectal cancer with or without the CpG island methylator phenotype (CIMP).

Science.gov (United States)

Hughes, Laura A E; Simons, Colinda C J M; van den Brandt, Piet A; Goldbohm, R Alexandra; de Goeij, Anton F; de Bruïne, Adriaan P; van Engeland, Manon; Weijenberg, Matty P

2011-04-05

We investigated how body size and physical activity influence the risk of the CpG island methylator phenotype (CIMP) in colorectal cancer (CRC). In the Netherlands Cohort Study (n = 120,852), risk factors were self-reported at baseline in 1986. After 7.3 years of follow-up, 603 cases and 4,631 sub-cohort members were available. CIMP status according to the Weisenberger markers was determined using methylation specific PCR on DNA from paraffin embedded tumor tissue. Hazard rate ratios (HR) and 95% confidence intervals for CIMP (27.7%) and non-CIMP (72.3%) tumors were calculated according to BMI, BMI at age 20, BMI change, trouser/skirt size, height, and physical activity. BMI modeled per 5 kg/m(2) increase was associated with both CIMP and non-CIMP tumors, however, HRs were attenuated when additionally adjusted for trouser/skirt size. Trouser/skirt size, per 2 size increase, was associated with both tumor subtypes, even after adjustment for BMI (CIMP HR: 1.20, 95%CI: 1.01-1.43; non-CIMP HR: 1.14, 95%CI: 1.04-1.28). Height per 5 cm was associated with both tumor sub-types, but HRs were attenuated when adjusted for body weight. BMI at age 20 was positively associated with increased risk of CIMP tumors and the association was significantly less pronounced for non-CIMP tumors (P-heterogeneity = 0.01). Physical activity was inversely associated with both subtypes, but a dose-response association was observed only for non-CIMP tumors (P-trend = 0.02). Body size, especially central adiposity, may increase the risk of both CIMP and non-CIMP tumors. Body fat at young age may differentially influence risk. Physical activity appears to decrease the risk of CRC regardless of these molecular subtypes.

Up-regulation of expression and lack of 5' CpG island hypermethylation of p16 INK4a in HPV-positive cervical carcinomas

Directory of Open Access Journals (Sweden)

Frank Georgy A

2007-03-01

Full Text Available Abstract Background High risk type human papilloma viruses (HR-HPV induce carcinomas of the uterine cervix by expressing viral oncogenes E6 and E7. Oncogene E7 of HR-HPV disrupts the pRb/E2F interaction, which negatively regulates the S phase entry. Expression of tumor suppressor p16ink4a drastically increases in majority of HR-HPV associated carcinomas due to removal of pRb repression. The p16ink4a overexpression is an indicator of an aberrant expression of viral oncogenes and may serve as a marker for early diagnostic of cervical cancer. On the other hand, in 25–57% of cervical carcinomas hypermethylation of the p16 INK4a promoter has been demonstrated using a methylation-specific PCR, MSP. To evaluate a potential usage of the p16 INK4a 5' CpG island hypermethylation as an indicator of tumor cell along with p16ink4a overexpression, we analyzed the methylation status of p16 INK4a in cervical carcinomas Methods Methylation status of p16 INK4a was analyzed by MSP and by bisulfite-modified DNA sequencing. The expression of p16ink4a was analyzed by RT-PCR and by immunohistochemical technique. Results The extensive methylation within p16 INK4a 5' CpG island was not detected either in 13 primary cervical carcinomas or in 5 cancer cell lines by bisulfite-modified DNA sequencing (including those that were positive by MSP in our hands. The number and distribution of rare partially methylated CpG sites did not differ considerably in tumors and adjacent normal tissues. The levels of the p16 INK4a mRNA were increased in carcinomas compared to the normal tissues independently of the number of partially methylated CpGs within 5'CpG island. The transcriptional activation of p16 INK4a was accompanied by p16ink4a cytoplasmic immunoreactivity in the majority of tumor cells and presence of a varied number of the p16 positive nuclei in different tumors. Conclusion Hypermethylaion of the p16INK4a 5' CpG island is not a frequent event in HR-HPV-positive cervical

Intraoperative non-record-keeping usage of anesthesia information management system workstations and associated hemodynamic variability and aberrancies.

Science.gov (United States)

Wax, David B; Lin, Hung-Mo; Reich, David L

2012-12-01

Anesthesia information management system workstations in the anesthesia workspace that allow usage of non-record-keeping applications could lead to distraction from patient care. We evaluated whether non-record-keeping usage of the computer workstation was associated with hemodynamic variability and aberrancies. Auditing data were collected on eight anesthesia information management system workstations and linked to their corresponding electronic anesthesia records to identify which application was active at any given time during the case. For each case, the periods spent using the anesthesia information management system record-keeping module were separated from those spent using non-record-keeping applications. The variability of heart rate and blood pressure were also calculated, as were the incidence of hypotension, hypertension, and tachycardia. Analysis was performed to identify whether non-record-keeping activity was a significant predictor of these hemodynamic outcomes. Data were analyzed for 1,061 cases performed by 171 clinicians. Median (interquartile range) non-record-keeping activity time was 14 (1, 38) min, representing 16 (3, 33)% of a median 80 (39, 143) min of procedure time. Variables associated with greater non-record-keeping activity included attending anesthesiologists working unassisted, longer case duration, lower American Society of Anesthesiologists status, and general anesthesia. Overall, there was no independent association between non-record-keeping workstation use and hemodynamic variability or aberrancies during anesthesia either between cases or within cases. Anesthesia providers spent sizable portions of case time performing non-record-keeping applications on anesthesia information management system workstations. This use, however, was not independently associated with greater hemodynamic variability or aberrancies in patients during maintenance of general anesthesia for predominantly general surgical and gynecologic procedures.

48 CFR 733.103-73 - Protests excluded from consideration.

Science.gov (United States)

2010-10-01

... 48 Federal Acquisition Regulations System 5 2010-10-01 2010-10-01 false Protests excluded from consideration. 733.103-73 Section 733.103-73 Federal Acquisition Regulations System AGENCY FOR INTERNATIONAL... excluded from consideration. (a) Contract administration. Disputes between a contractor and USAID are...

Local therapy with CpG motifs in a murine model of allergic airway inflammation in IFN-beta knock-out mice

DEFF Research Database (Denmark)

Matheu, Victor; Treschow, Alexandra; Teige, Ingrid

2005-01-01

BACKGROUND: CpG oligodeoxynucleotides (CpG-ODN) are capable of inducing high amounts of type I IFNs with many immunomodulatory properties. Furthermore, type-I IFNs have been proposed to play a key role in mediating effects of CpG-ODN. The precise role of IFN-beta in the immunomodulatory effects o...

The core element of a CpG island protects avian sarcoma and leukosis virus-derived vectors from transcriptional silencing

Czech Academy of Sciences Publication Activity Database

Šenigl, Filip; Plachý, Jiří; Hejnar, Jiří

2008-01-01

Roč. 82, č. 16 (2008), s. 7818-7827 ISSN 0022-538X R&D Projects: GA ČR GA204/05/0939; GA ČR GA523/07/1171 Institutional research plan: CEZ:AV0Z50520514 Keywords : anti-methylation protection * retroviral vector * CpG island Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 5.308, year: 2008

A stable nanoparticulate DDA/MMG formulation acts synergistically with CpG ODN 1826 to enhance the CD4(+) T-cell response

DEFF Research Database (Denmark)

Karlsen, Kasper; Korsholm, Karen Smith; Mortensen, Rasmus

2014-01-01

AIM: To combine the dimethyldioctadecyl ammonium/monomycoloyl glycerol (DDA/MMG) liposomal vaccine adjuvant with the Toll-like receptor (TLR) ligands poly(I:C) (TLR3), flagellin (TLR5) or CpG oligodeoxynucleotide 1826 (TLR9) and investigate their physicochemical properties as well as their CD4(+)...

Respiratory induced heart rate variability during slow mechanical ventilation Marker to exclude brain death patients

Czech Academy of Sciences Publication Activity Database

Jurák, Pavel; Halámek, Josef; Vondra, Vlastimil; Kružliak, P.; Šrámek, V.; Cundrle, I.; Leinveber, P.; Adamek, M.; Zvoníček, V.

2017-01-01

Roč. 129, 7-8 (2017), s. 251-258 ISSN 0043-5325 R&D Projects: GA ČR GAP103/11/0933; GA MŠk(CZ) LO1212; GA MŠk ED0017/01/01; GA MZd NS10105 Institutional support: RVO:68081731 Keywords : critical illness * sedation * brain death * respiratory rate variability * heart rate variability * mechanical ventilation Subject RIV: FS - Medical Facilities ; Equipment OBOR OECD: Medical engineering Impact factor: 0.974, year: 2016

Genome-wide CpG island methylation analysis implicates novel genes in the pathogenesis of renal cell carcinoma

OpenAIRE

Ricketts, Christopher J.; Morris, Mark R.; Gentle, Dean; Brown, Michael; Wake, Naomi; Woodward, Emma R.; Clarke, Noel; Latif, Farida; Maher, Eamonn R.

2012-01-01

In order to identify novel candidate tumor suppressor genes (TSGs) implicated in renal cell carcinoma (RCC), we performed genome-wide methylation profiling of RCC using the HumanMethylation27 BeadChips to assess methylation at >14,000 genes. Two hundred and twenty hypermethylated probes representing 205 loci/genes were identified in genomic CpG islands. A subset of TSGs investigated in detail exhibited frequent tumor methylation, promoter methylation associated transcriptional silencing an...

Alternative preparation of inclusion bodies excludes interfering non-protein contaminants and improves the yield of recombinant proinsulin.

Science.gov (United States)

Mackin, Robert B

2014-01-01

The goal of simple, high-yield expression and purification of recombinant human proinsulin has proven to be a considerable challenge. First, proinsulin forms inclusion bodies during bacterial expression. While this phenomenon can be exploited as a capture step, conventionally prepared inclusion bodies contain significant amounts of non-protein contaminants that interfere with subsequent chromatographic purification. Second, the proinsulin molecules within the inclusion bodies are incorrectly folded, and likely cross-linked to one another, making it difficult to quantify the amount of expressed proinsulin. Third, proinsulin is an intermediate between the initial product of ribosomal translation (preproinsulin) and the final product secreted by pancreatic beta cells (insulin). Therefore, to be efficiently produced in bacteria, it must be produced as an N-terminally extended fusion protein, which has to be converted to authentic proinsulin during the purification scheme. To address all three of these problems, while simultaneously streamlining the procedure and increasing the yield of recombinant proinsulin, we have made three substantive modifications to our previous method for producing proinsulin:.•Conditions for the preparation of inclusion bodies have been altered so contaminants that interfere with semi-preparative reversed-phase chromatography are excluded while the proinsulin fusion protein is retained at high yield.•Aliquots are taken following important steps in the procedure and the quantity of proinsulin-related polypeptide in the sample is compared to the amount present prior to that step.•Final purification is performed using a silica-based reversed-phase matrix in place of a polystyrene-divinylbenzene-based matrix.

Glucocorticoid receptor gene expression and promoter CpG modifications throughout the human brain.

Science.gov (United States)

Cao-Lei, Lei; Suwansirikul, Songkiet; Jutavijittum, Prapan; Mériaux, Sophie B; Turner, Jonathan D; Muller, Claude P

2013-11-01

Glucocorticoids and the glucocorticoid (GR) and mineralocorticoid (MR) receptors have been implicated in many processes, particularly in negative feedback regulation of the hypothalamic-pituitary-adrenal axis. Epigenetically programmed GR alternative promoter usage underlies transcriptional control of GR levels, generation of GR 3' splice variants, and the overall GC response in the brain. No detailed analysis of GR first exons or GR transcript variants throughout the human brain has been reported. Therefore we investigated post mortem tissues from 28 brain regions of 5 individuals. GR first exons were expressed throughout the healthy human brain with no region-specific usage patterns. First exon levels were highly inter-correlated suggesting that they are co-regulated. GR 3' splice variants (GRα and GR-P) were equally distributed in all regions, and GRβ expression was always low. GR/MR ratios showed significant differences between the 28 tissues with the highest ratio in the pituitary gland. Modification levels of individual CpG dinucleotides, including 5-mC and 5-hmC, in promoters 1D, 1E, 1F, and 1H were low, and diffusely clustered; despite significant heterogeneity between the donors. In agreement with this clustering, sum modification levels rather than individual CpG modifications correlated with GR expression. Two-way ANOVA showed that this sum modification was both promoter and brain region specific, but that there was however no promoter*tissue interaction. The heterogeneity between donors may however hide such an interaction. In both promoters 1F and 1H modification levels correlated with GRα expression suggesting that 5-mC and 5-hmC play an important role in fine tuning GR expression levels throughout the brain. Copyright © 2013 Elsevier Ltd. All rights reserved.

Inactivation of Adenomatous Polyposis Coli Reduces Bile Acid/Farnesoid X Receptor Expression through Fxr gene CpG Methylation in Mouse Colon Tumors and Human Colon Cancer Cells.

Science.gov (United States)

Selmin, Ornella I; Fang, Changming; Lyon, Adam M; Doetschman, Tom C; Thompson, Patricia A; Martinez, Jesse D; Smith, Jeffrey W; Lance, Peter M; Romagnolo, Donato F

2016-02-01

The farnesoid X receptor (FXR) regulates bile acid (BA) metabolism and possesses tumor suppressor functions. FXR expression is reduced in colorectal tumors of subjects carrying inactivated adenomatous polyposis coli (APC). Identifying the mechanisms responsible for this reduction may offer new molecular targets for colon cancer prevention. We investigated how APC inactivation influences the regulation of FXR expression in colonic mucosal cells. We hypothesized that APC inactivation would epigenetically repress nuclear receptor subfamily 1, group H, member 4 (FXR gene name) expression through increased CpG methylation. Normal proximal colonic mucosa and normal-appearing adjacent colonic mucosa and colon tumors were collected from wild-type C57BL/6J and Apc-deficient (Apc(Min) (/+)) male mice, respectively. The expression of Fxr, ileal bile acid-binding protein (Ibabp), small heterodimer partner (Shp), and cyclooxygenase-2 (Cox-2) were determined by real-time polymerase chain reaction. In both normal and adjacent colonic mucosa and colon tumors, we measured CpG methylation of Fxr in bisulfonated genomic DNA. In vitro, we measured the impact of APC inactivation and deoxycholic acid (DCA) treatment on FXR expression in human colon cancer HCT-116 cells transfected with silencing RNA for APC and HT-29 cells carrying inactivated APC. In Apc(Min) (/+) mice, constitutive CpG methylation of the Fxrα3/4 promoter was linked to reduced (60-90%) baseline Fxr, Ibabp, and Shp and increased Cox-2 expression in apparently normal adjacent mucosa and colon tumors. Apc knockdown in HCT-116 cells increased cellular myelocytomatosis (c-MYC) and lowered (∼50%) FXR expression, which was further reduced (∼80%) by DCA. In human HCT-116 but not HT-29 colon cancer cells, DCA induced FXR expression and lowered CpG methylation of FXR. We conclude that the loss of APC function favors the silencing of FXR expression through CpG hypermethylation in mouse colonic mucosa and human colon cells

Excluded Volume Effects in Gene Stretching

OpenAIRE

Lam, Pui-Man

2002-01-01

We investigate the effects excluded volume on the stretching of a single DNA in solution. We find that for small force F, the extension h is not linear in F but proportion to F^{\\chi}, with \\chi=(1-\

The relationship between gait variability and cognitive functions differs between fallers and non-fallers in MS.

Science.gov (United States)

Kalron, Alon; Aloni, Roy; Dolev, Mark; Frid, Lior; Givon, Uri; Menascu, Shay

2018-01-19

The objective of the study was to determine if cognitive function is associated with step time variability in people with multiple sclerosis (PwMS). The study included 355 PwMS (218 women), average age 41.1 (SD = 13.5), disease duration 5.9 (SD = 7.3) years, and a median expanded disability status scale score of 2.5. We separately analyzed the sample group of fallers and non-fallers based on their fall history. Gait variability was measured by an electronic walkway and all participants completed a computerized cognitive test battery designed to evaluate multiple cognitive domains. Fallers (43.7%) demonstrated elevated step time variability (%CV), 5.0 (SD = 3.4) vs. 3.5 (SD = 1.6), P < 0.001 compared to the non-faller subjects. According to the regression analysis in the non-fallers' group, step time variability was found significantly associated with the global cognitive score (P = 0.001), executive function subcategory (P = 0.038), and motor skills subcategory (P < 0.001). No relationship between step time variability and any cognitive domain was demonstrated in the faller group. This study illustrated that the association between gait variability and cognition occurs only in PwMS without a fall history. From a clinical standpoint, these findings might help medical professionals to create improved assessment tests and rehabilitation strategies in the MS population.

Non-uniform approximations for sums of discrete m-dependent random variables

OpenAIRE

Vellaisamy, P.; Cekanavicius, V.

2013-01-01

Non-uniform estimates are obtained for Poisson, compound Poisson, translated Poisson, negative binomial and binomial approximations to sums of of m-dependent integer-valued random variables. Estimates for Wasserstein metric also follow easily from our results. The results are then exemplified by the approximation of Poisson binomial distribution, 2-runs and $m$-dependent $(k_1,k_2)$-events.

Disclosing bias in bisulfite assay: MethPrimers underestimate high DNA methylation.

Directory of Open Access Journals (Sweden)

Andrea Fuso

Full Text Available Discordant results obtained in bisulfite assays using MethPrimers (PCR primers designed using MethPrimer software or assuming that non-CpGs cytosines are non methylated versus primers insensitive to cytosine methylation lead us to hypothesize a technical bias. We therefore used the two kinds of primers to study different experimental models and methylation statuses. We demonstrated that MethPrimers negatively select hypermethylated DNA sequences in the PCR step of the bisulfite assay, resulting in CpG methylation underestimation and non-CpG methylation masking, failing to evidence differential methylation statuses. We also describe the characteristics of "Methylation-Insensitive Primers" (MIPs, having degenerated bases (G/A to cope with the uncertain C/U conversion. As CpG and non-CpG DNA methylation patterns are largely variable depending on the species, developmental stage, tissue and cell type, a variable extent of the bias is expected. The more the methylome is methylated, the greater is the extent of the bias, with a prevalent effect of non-CpG methylation. These findings suggest a revision of several DNA methylation patterns so far documented and also point out the necessity of applying unbiased analyses to the increasing number of epigenomic studies.

A polyethylenimine-modified carboxyl-poly(styrene/acrylamide copolymer nanosphere for co-delivering of CpG and TGF-β receptor I inhibitor with remarkable additive tumor regression effect against liver cancer in mice

Directory of Open Access Journals (Sweden)

Liang SY

2016-12-01

Full Text Available Shuyan Liang,* Jun Hu,* Yuanyuan Xie, Qing Zhou, Yanhong Zhu, Xiangliang Yang National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, People’s Republic of China *These authors contributed equally to this work Abstract: Cancer immunotherapy based on nanodelivery systems has shown potential for treatment of various malignancies, owing to the benefits of tumor targeting of nanoparticles. However, induction of a potent T-cell immune response against tumors still remains a challenge. In this study, polyethylenimine-modified carboxyl-styrene/acrylamide (PS copolymer nanospheres were developed as a delivery system of unmethylated cytosine-phosphate-guanine (CpG oligodeoxynucleotides and transforming growth factor-beta (TGF-β receptor I inhibitors for cancer immunotherapy. TGF-β receptor I inhibitors (LY2157299, LY were encapsulated to the PS via hydrophobic interaction, while CpG oligodeoxynucleotides were loaded onto the PS through electrostatic interaction. Compared to the control group, tumor inhibition in the PS-LY/CpG group was up to 99.7% without noticeable toxicity. The tumor regression may be attributed to T-cell activation and amplification in mouse models. The results highlight the additive effect of CpG and TGF-β receptor I inhibitors co-delivered in cancer immunotherapy. Keywords: CpG, TGF-β receptor I inhibitor, Pst-AAm copolymer nanosphere, immunotherapy

The effect of macroeconomic variables on non performance financing of Islamic Banks in Indonesia

Directory of Open Access Journals (Sweden)

Latifah Dian Iriani

2015-10-01

Full Text Available This research is going to discuss about the determinant macro variables and bank’s behavior determinant credit risk on Islamic rural bank in Indonesia. It could be seen on macro variables such as inflation, exchange rate, Jakarta I slamic index (JII and money supply (M2, and bank’s behavior such as financing. Research methodology used at this study is Vector Error Correction Model (VECM. Following these procedures, it applies Unit Roots Test, Augmented Dickey Fuller Test, Lag Length Criteria Test, Correlation Matrix – Johansen Julius Co-integration Test, VECM Estimation, Impulse Response and Variance Decomposition Test. The result show that both bank behaviors and macroeconomic variables are significant affecting non-performing financing (NPF. The banking need more careful to manage internal and external factors that influence non-performing financing (NPF.

Differential environmental exposure among non-Indigenous Canadians as a function of sex/gender and race/ethnicity variables: a scoping review.

Science.gov (United States)

Chakravartty, Dolon; Wiseman, Clare L S; Cole, Donald C

2014-11-21

To determine the extent, range and types of studies of differential environmental chemical exposures among non-Indigenous Canadians as a function of sex/gender and race/ethnicity. Computerized database searches were performed from November to December 2013 using Medline, Embase, CAB Abstracts, Proquest and Scopus to identify relevant studies of environmental exposures among non-Indigenous adults aged ≥18 years in Canada published between 1993 and 2013. Articles were identified for full-text review based on a screening of titles and abstracts and were excluded during this initial review if they focused on environmental exposures in the following populations: 1) Indigenous populations, 2) individuals <15 years of age, 3) pregnant women and associated negative birth outcomes, or 4) non-Canadian populations. Articles were also excluded if the primary focus was on exposures to environmental tobacco smoke, non-chemical occupational hazards, infectious diseases, noise and/or radiation. A full-text review of 78 identified articles systematically assessed how sex/gender and race/ethnicity were considered. Although 59% of studies stratified results by sex, less than half of these offered any explanation of differential exposures. Eighteen of the 78 studies (23%) used terms related to race/ethnicity in their participant descriptions. Of the studies that conducted subgroup analyses of exposure results by race/ethnicity (n=15), a total of 8 also included subgroup analysis by sex. Overall, 3 of the 78 (3%) articles reviewed analyzed environmental exposures as a function of sex/gender and race/ethnicity. The role of sex/gender and race/ethnicity in influencing environmental exposure levels among non-Indigenous Canadians has not been adequately addressed to date.

Quantum key distribution using continuous-variable non-Gaussian states

Science.gov (United States)

Borelli, L. F. M.; Aguiar, L. S.; Roversi, J. A.; Vidiella-Barranco, A.

2016-02-01

In this work, we present a quantum key distribution protocol using continuous-variable non-Gaussian states, homodyne detection and post-selection. The employed signal states are the photon added then subtracted coherent states (PASCS) in which one photon is added and subsequently one photon is subtracted from the field. We analyze the performance of our protocol, compared with a coherent state-based protocol, for two different attacks that could be carried out by the eavesdropper (Eve). We calculate the secret key rate transmission in a lossy line for a superior channel (beam-splitter) attack, and we show that we may increase the secret key generation rate by using the non-Gaussian PASCS rather than coherent states. We also consider the simultaneous quadrature measurement (intercept-resend) attack, and we show that the efficiency of Eve's attack is substantially reduced if PASCS are used as signal states.

Non-Markovian entanglement dynamics of noisy continuous-variable quantum channels

International Nuclear Information System (INIS)

An, J.-H.; Zhang, W.-M.

2007-01-01

We investigate the entanglement dynamics of continuous-variable quantum channels in terms of an entangled squeezed state of two cavity fields in a general non-Markovian environment. Using the Feynman-Vernon influence functional theory in the coherent-state representation, we derive an exact master equation with time-dependent coefficients reflecting the non-Markovian influence of the environment. The influence of environments with different spectral densities, e.g., Ohmic, sub-Ohmic, and super-Ohmic, is numerically studied. The non-Markovian process shows its remarkable influence on the entanglement dynamics due to the sensitive time dependence of the dissipation and noise functions within the typical time scale of the environment. The Ohmic environment shows a weak dissipation-noise effect on the entanglement dynamics, while the sub-Ohmic and super-Ohmic environments induce much more severe noise. In particular, the memory of the system interacting with the environment contributes a strong decoherence effect to the entanglement dynamics in the super-Ohmic case

Excluded segmental duct bile leakage: the case for bilio-enteric anastomosis.

Science.gov (United States)

Patrono, Damiano; Tandoi, Francesco; Romagnoli, Renato; Salizzoni, Mauro

2014-06-01

Excluded segmental duct bile leak is the rarest type of post-hepatectomy bile leak and presents unique diagnostic and management features. Classical management strategies invariably entail a significant loss of functioning hepatic parenchyma. The aim of this study is to report a new liver-sparing technique to handle excluded segmental duct bile leakage. Two cases of excluded segmental duct bile leak occurring after major hepatic resection were managed by a Roux-en-Y hepatico-jejunostomy on the excluded segmental duct, avoiding the sacrifice of the liver parenchyma origin of the fistula. In both cases, classical management strategies would have led to the functional loss of roughly 50 % of the liver remnant. Diagnostic and management implications are thoroughly discussed. Both cases had an uneventful postoperative course. The timing of repair was associated with a different outcome: the patient who underwent surgical repair in the acute phase developed no long-term complications, whereas the patient who underwent delayed repair developed a late stenosis requiring percutaneous dilatation. Roux-en-Y hepatico-jejunostomy on the excluded bile duct is a valuable technique in selected cases of excluded segmental duct bile leakage.

Characterizing the strand-specific distribution of non-CpG methylation in human pluripotent cells

OpenAIRE

Guo, Weilong; Chung, Wen-Yu; Qian, Minping; Pellegrini, Matteo; Zhang, Michael Q.

2013-01-01

DNA methylation is an important defense and regulatory mechanism. In mammals, most DNA methylation occurs at CpG sites, and asymmetric non-CpG methylation has only been detected at appreciable levels in a few cell types. We are the first to systematically study the strand-specific distribution of non-CpG methylation. With the divide-and-compare strategy, we show that CHG and CHH methylation are not intrinsically different in human embryonic stem cells (ESCs) and induced pluripotent stem cells...

The Matrix model, a driven state variables approach to non-equilibrium thermodynamics

NARCIS (Netherlands)

Jongschaap, R.J.J.

2001-01-01

One of the new approaches in non-equilibrium thermodynamics is the so-called matrix model of Jongschaap. In this paper some features of this model are discussed. We indicate the differences with the more common approach based upon internal variables and the more sophisticated Hamiltonian and GENERIC

B-cell activation with CD40L or CpG measures the function of B-cell subsets and identifies specific defects in immunodeficient patients.

Science.gov (United States)

Marasco, Emiliano; Farroni, Chiara; Cascioli, Simona; Marcellini, Valentina; Scarsella, Marco; Giorda, Ezio; Piano Mortari, Eva; Leonardi, Lucia; Scarselli, Alessia; Valentini, Diletta; Cancrini, Caterina; Duse, Marzia; Grimsholm, Ola; Carsetti, Rita

2017-01-01

Around 65% of primary immunodeficiencies are antibody deficiencies. Functional tests are useful tools to study B-cell functions in vitro. However, no accepted guidelines for performing and evaluating functional tests have been issued yet. Here, we report our experience on the study of B-cell functions in infancy and throughout childhood. We show that T-independent stimulation with CpG measures proliferation and differentiation potential of memory B cells. Switched memory B cells respond better than IgM memory B cells. On the other hand, CD40L, a T-dependent stimulus, does not induce plasma cell differentiation, but causes proliferation of naïve and memory B cells. During childhood, the production of plasmablasts in response to CpG increases with age mirroring the development of memory B cells. The response to CD40L does not change with age. In patients with selective IgA deficiency (SIgAD), we observed that switched memory B cells are reduced due to the absence of IgA memory B cells. In agreement, IgA plasma cells are not generated in response to CpG. Unexpectedly, B cells from SIgAD patients show a reduced proliferative response to CD40L. Our results demonstrate that functional tests are an important tool to assess the functions of the humoral immune system. © 2016 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The Value of the Right to Exclude: An Empirical Assessment

NARCIS (Netherlands)

J.M. Klick (Jonathan); G. Parchomovsky (Gideon)

2016-01-01

markdownabstractProperty theorists have long deemed the right to exclude fundamental and essential for the efficient use and allocation of property. Recently, however, proponents of the progressive property movement have called into question the centrality of the right to exclude, suggesting that it

8 CFR 241.21 - Stay of deportation of excluded alien.

Science.gov (United States)

2010-01-01

... 8 Aliens and Nationality 1 2010-01-01 2010-01-01 false Stay of deportation of excluded alien. 241.21 Section 241.21 Aliens and Nationality DEPARTMENT OF HOMELAND SECURITY IMMIGRATION REGULATIONS APPREHENSION AND DETENTION OF ALIENS ORDERED REMOVED Deportation of Excluded Aliens (for Hearings Commenced...

Comprehensive biostatistical analysis of CpG island methylator phenotype in colorectal cancer using a large population-based sample.

Directory of Open Access Journals (Sweden)

Katsuhiko Nosho

Full Text Available The CpG island methylator phenotype (CIMP is a distinct phenotype associated with microsatellite instability (MSI and BRAF mutation in colon cancer. Recent investigations have selected 5 promoters (CACNA1G, IGF2, NEUROG1, RUNX3 and SOCS1 as surrogate markers for CIMP-high. However, no study has comprehensively evaluated an expanded set of methylation markers (including these 5 markers using a large number of tumors, or deciphered the complex clinical and molecular associations with CIMP-high determined by the validated marker panel. METHOLODOLOGY/PRINCIPAL FINDINGS: DNA methylation at 16 CpG islands [the above 5 plus CDKN2A (p16, CHFR, CRABP1, HIC1, IGFBP3, MGMT, MINT1, MINT31, MLH1, p14 (CDKN2A/ARF and WRN] was quantified in 904 colorectal cancers by real-time PCR (MethyLight. In unsupervised hierarchical clustering analysis, the 5 markers (CACNA1G, IGF2, NEUROG1, RUNX3 and SOCS1, CDKN2A, CRABP1, MINT31, MLH1, p14 and WRN were generally clustered with each other and with MSI and BRAF mutation. KRAS mutation was not clustered with any methylation marker, suggesting its association with a random methylation pattern in CIMP-low tumors. Utilizing the validated CIMP marker panel (including the 5 markers, multivariate logistic regression demonstrated that CIMP-high was independently associated with older age, proximal location, poor differentiation, MSI-high, BRAF mutation, and inversely with LINE-1 hypomethylation and beta-catenin (CTNNB1 activation. Mucinous feature, signet ring cells, and p53-negativity were associated with CIMP-high in only univariate analysis. In stratified analyses, the relations of CIMP-high with poor differentiation, KRAS mutation and LINE-1 hypomethylation significantly differed according to MSI status.Our study provides valuable data for standardization of the use of CIMP-high-specific methylation markers. CIMP-high is independently associated with clinical and key molecular features in colorectal cancer. Our data also

21 CFR 1310.08 - Excluded transactions.

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2010-04-01

... 21 Food and Drugs 9 2010-04-01 2010-04-01 false Excluded transactions. 1310.08 Section 1310.08 Food and Drugs DRUG ENFORCEMENT ADMINISTRATION, DEPARTMENT OF JUSTICE RECORDS AND REPORTS OF LISTED...) Colombia (6) Ecuador (7) French Guiana (8) Guyana (9) Panama (10) Paraguay (11) Peru (12) Suriname (13...

42 CFR 403.768 - Excluded services.

Science.gov (United States)

2010-10-01

... a RNHCI. (c) A nurse who is not providing RNHCI home nursing services under arrangement with a RNHCI... 42 Public Health 2 2010-10-01 2010-10-01 false Excluded services. 403.768 Section 403.768 Public Health CENTERS FOR MEDICARE & MEDICAID SERVICES, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL...

Treatment of Tobacco Dependence, a Critical Gap in Czech Clinical Practice Guidelines.

Science.gov (United States)

Zvolská, Kamila; Fraser, Keely; Zvolský, Miroslav; Králíková, Eva

2017-06-01

Tobacco related comorbidities and treatment of dependence are relevant to clinicians of all disciplines. Clinicians should provide a brief intervention about tobacco use with smokers at each clinical contact (success rate of 5-10 %). Intensive treatment (success rate >30%) should be available to those who need it. Brief intervention is not yet standard clinical practice. Our aim was to assess clinical practice guidelines (CPG) of selected medical professional societies to determine whether or not tobacco dependence treatment recommendations were included. Between October and December 2013, we conducted a keyword search of CPG for 20 medical professional societies in the Czech Republic. We searched for the keywords "smoking", "tobacco" and "nicotine addiction" in 91 CPG documents, which were freely available on the websites of selected professional societies. We focused specifically on CPG relating to cardiovascular and respiratory diseases as well as cancer. We excluded any CPG focused on acute conditions, diagnostics only, laboratory methods, or administration. There was no mention of smoking in 27.7% (26/94) of CPG documents. Only 16% (15/94) of CPG documents listed smoking as a risk factor. 42.5% (40/94) mentioned smoking related phrases (e.g. "smoking ban"). Only 13.8% (13/94) of CPG included a section on tobacco dependence, referenced tobacco dependence treatment guidelines or mentioned specialized treatment centres where smokers can be referred. Nearly one third of CPG related to cardiovascular and respiratory diseases as well as cancer made no mention of smoking. Despite the clinical significance of smoking, the majority of CPG did not adequately address tobacco dependence and its treatment. Copyright© by the National Institute of Public Health, Prague 2017

22 CFR 40.102 - Guardian required to accompany excluded alien.

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2010-04-01

... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Guardian required to accompany excluded alien. 40.102 Section 40.102 Foreign Relations DEPARTMENT OF STATE VISAS REGULATIONS PERTAINING TO BOTH... Guardian required to accompany excluded alien. INA 212(a)(9)(B) is not applicable at the time of visa...

Epigenetic regulation of CpG promoter methylation in invasive prostate cancer cells

Directory of Open Access Journals (Sweden)

Farrar William L

2010-10-01

Full Text Available Abstract Background Recently, much attention has been focused on gaining a better understanding of the different populations of cells within a tumor and their contribution to cancer progression. One of the most commonly used methods to isolate a more aggressive sub-population of cells utilizes cell sorting based on expression of certain cell adhesion molecules. A recently established method we developed is to isolate these more aggressive cells based on their properties of increased invasive ability. These more invasive cells have been previously characterized as tumor initiating cells (TICs that have a stem-like genomic signature and express a number of stem cell genes including Oct3/4 and Nanog and are more tumorigenic compared to their 'non-invasive' counterpart. They also have a profile reminiscent of cells undergoing a classic pattern of epithelial to mesenchymal transition or EMT. Using this model of invasion, we sought to investigate which genes are under epigenetic control in this rare population of cells. Epigenetic modifications, specifically DNA methylation, are key events regulating the process of normal human development. To determine the specific methylation pattern in these invasive prostate cells, and if any developmental genes were being differentially regulated, we analyzed differences in global CpG promoter methylation. Results Differentially methylated genes were determined and select genes were chosen for additional analyses. The non-receptor tyrosine kinase BMX and transcription factor SOX1 were found to play a significant role in invasion. Ingenuity pathway analysis revealed the methylated gene list frequently displayed genes from the IL-6/STAT3 pathway. Cells which have decreased levels of the targets BMX and SOX1 also display loss of STAT3 activity. Finally, using Oncomine, it was determined that more aggressive metastatic prostate cancers in humans also have higher levels of both Stat3 and Sox1. Conclusions Using this

Human Vav1 expression in hematopoietic and cancer cell lines is regulated by c-Myb and by CpG methylation.

Directory of Open Access Journals (Sweden)

Lena Ilan

Full Text Available Vav1 is a signal transducer protein that functions as a guanine nucleotide exchange factor for the Rho/Rac GTPases in the hematopoietic system where it is exclusively expressed. Recently, Vav1 was shown to be involved in several human malignancies including neuroblastoma, lung cancer, and pancreatic ductal adenocarcinoma (PDA. Although some factors that affect vav1 expression are known, neither the physiological nor pathological regulation of vav1 expression is completely understood. We demonstrate herein that mutations in putative transcription factor binding sites at the vav1 promoter affect its transcription in cells of different histological origin. Among these sites is a consensus site for c-Myb, a hematopoietic-specific transcription factor that is also found in Vav1-expressing lung cancer cell lines. Depletion of c-Myb using siRNA led to a dramatic reduction in vav1 expression in these cells. Consistent with this, co-transfection of c-Myb activated transcription of a vav1 promoter-luciferase reporter gene construct in lung cancer cells devoid of Vav1 expression. Together, these results indicate that c-Myb is involved in vav1 expression in lung cancer cells. We also explored the methylation status of the vav1 promoter. Bisulfite sequencing revealed that the vav1 promoter was completely unmethylated in human lymphocytes, but methylated to various degrees in tissues that do not normally express vav1. The vav1 promoter does not contain CpG islands in proximity to the transcription start site; however, we demonstrated that methylation of a CpG dinucleotide at a consensus Sp1 binding site in the vav1 promoter interferes with protein binding in vitro. Our data identify two regulatory mechanisms for vav1 expression: binding of c-Myb and CpG methylation of 5' regulatory sequences. Mutation of other putative transcription factor binding sites suggests that additional factors regulate vav1 expression as well.

Broadband non-polarizing terahertz beam splitters with variable split ratio

KAUST Repository

Wei, Minggui

2017-08-15

Seeking effective terahertz functional devices has always aroused extensive attention. Of particular interest is the terahertz beam splitter. Here, we have proposed, designed, manufactured, and tested a broadband non-polarizing terahertz beam splitter with a variable split ratio based on an all-dielectric metasurface. The metasurface was created by patterning a dielectric surface of the N-step phase gradient and etching to a few hundred micrometers. The conversion efficiency as high as 81% under the normal incidence at 0.7 THz was achieved. Meanwhile, such a splitter works well over a broad frequency range. The split ratio of the proposed design can be continuously tuned by simply shifting the metasurface, and the angle of emergences can also be easily adjusted by choosing the step of phase gradients. The proposed design is non-polarizing, and its performance is kept under different polarizations.

Broadband non-polarizing terahertz beam splitters with variable split ratio

Science.gov (United States)

Wei, Minggui; Xu, Quan; Wang, Qiu; Zhang, Xueqian; Li, Yanfeng; Gu, Jianqiang; Tian, Zhen; Zhang, Xixiang; Han, Jiaguang; Zhang, Weili

2017-08-01

Seeking effective terahertz functional devices has always aroused extensive attention. Of particular interest is the terahertz beam splitter. Here, we have proposed, designed, manufactured, and tested a broadband non-polarizing terahertz beam splitter with a variable split ratio based on an all-dielectric metasurface. The metasurface was created by patterning a dielectric surface of the N-step phase gradient and etching to a few hundred micrometers. The conversion efficiency as high as 81% under the normal incidence at 0.7 THz was achieved. Meanwhile, such a splitter works well over a broad frequency range. The split ratio of the proposed design can be continuously tuned by simply shifting the metasurface, and the angle of emergences can also be easily adjusted by choosing the step of phase gradients. The proposed design is non-polarizing, and its performance is kept under different polarizations.

Broadband non-polarizing terahertz beam splitters with variable split ratio

KAUST Repository

Wei, Minggui; Xu, Quan; Wang, Qiu; Zhang, Xueqian; Li, Yanfeng; Gu, Jianqiang; Tian, Zhen; Zhang, Xixiang; Han, Jiaguang; Zhang, Weili

2017-01-01

Seeking effective terahertz functional devices has always aroused extensive attention. Of particular interest is the terahertz beam splitter. Here, we have proposed, designed, manufactured, and tested a broadband non-polarizing terahertz beam splitter with a variable split ratio based on an all-dielectric metasurface. The metasurface was created by patterning a dielectric surface of the N-step phase gradient and etching to a few hundred micrometers. The conversion efficiency as high as 81% under the normal incidence at 0.7 THz was achieved. Meanwhile, such a splitter works well over a broad frequency range. The split ratio of the proposed design can be continuously tuned by simply shifting the metasurface, and the angle of emergences can also be easily adjusted by choosing the step of phase gradients. The proposed design is non-polarizing, and its performance is kept under different polarizations.

Randomized phase II study of paclitaxel/carboplatin intercalated with gefitinib compared to paclitaxel/carboplatin alone for chemotherapy-naïve non-small cell lung cancer in a clinically selected population excluding patients with non-smoking adenocarcinoma or mutated EGFR

International Nuclear Information System (INIS)

Choi, Yoon Ji; Lee, Dae Ho; Choi, Chang Min; Lee, Jung Shin; Lee, Seung Jin; Ahn, Jin-Hee; Kim, Sang-We

2015-01-01

Considering cell cycle dependent cytotoxicity, intercalation of chemotherapy and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) may be a treatment option in non-small cell lung cancer (NSCLC). This randomized phase 2 study compared the efficacy of paclitaxel and carboplatin (PC) intercalated with gefitinib (G) versus PC alone in a selected, chemotherapy-naïve population of advanced NSCLC patients with a history of smoking or wild-type EGFR. Eligible patients were chemotherapy-naïve advanced NSCLC patients with Eastern Cooperative Oncology Group performance status of 0—2. Non-smoking patients with adenocarcinoma or patients with activating EGFR mutation were excluded because they could benefit from gefitinib alone. Eligible patients were randomized to one of the following treatment arms: PCG, P 175 mg/m 2 , and C AUC 5 administered intravenously on day 1 intercalated with G 250 mg orally on days 2 through 15 every 3 weeks for four cycles followed by G 250 mg orally until progressive disease; or PC, same dosing schedule for four cycles only. The primary endpoint was the objective response rate (ORR), and the secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity profile. A total of 90 patients participated in the study. The ORRs were 41.9 % (95 % confidence interval (CI) 27.0–57.9 %) for the PCG arm and 39.5 % (95 % CI 25.0–55.6 %) for the PC arm (P = 0.826). No differences in PFS (4.1 vs. 4.1 months, P = 0.781) or OS (9.3 vs. 10.5 months, P = 0.827) were observed between the PCG and PC arms. Safety analyses showed a similar incidence of drug-related grade 3/4 toxicity. Rash and pruritus were more frequent in the PCG than in the PC arm. PCG did not improve ORR, PFS, and OS compared to PC chemotherapy alone for NSCLC in a clinically selected population excluding non-smoking adenocarcinoma or mutated EGFR. The study is registered with ClinicalTrials.gov (NCT01196234). Registration date is 08/09/2010

A CpG island methylator phenotype of colorectal cancer that is contiguous with conventional adenomas, but not serrated polyps

OpenAIRE

HOKAZONO, KOJI; UEKI, TAKASHI; NAGAYOSHI, KINUKO; NISHIOKA, YASUNOBU; HATAE, TATSUNOBU; KOGA, YUTAKA; HIRAHASHI, MINAKO; ODA, YOSHINAO; TANAKA, MASAO

2014-01-01

A subset of colorectal cancers (CRCs) harbor the CpG island methylator phenotype (CIMP), with concurrent multiple promoter hypermethylation of tumor-related genes. A serrated pathway in which CIMP is developed from serrated polyps is proposed. The present study characterized CIMP and morphologically examined precursor lesions of CIMP. In total, 104 CRCs treated between January 1996 and December 2004 were examined. Aberrant promoter methylation of 15 cancer-related genes was analyzed. CIMP sta...

Developing a spatial-statistical model and map of historical malaria prevalence in Botswana using a staged variable selection procedure

Directory of Open Access Journals (Sweden)

Mabaso Musawenkosi LH

2007-09-01

Full Text Available Abstract Background Several malaria risk maps have been developed in recent years, many from the prevalence of infection data collated by the MARA (Mapping Malaria Risk in Africa project, and using various environmental data sets as predictors. Variable selection is a major obstacle due to analytical problems caused by over-fitting, confounding and non-independence in the data. Testing and comparing every combination of explanatory variables in a Bayesian spatial framework remains unfeasible for most researchers. The aim of this study was to develop a malaria risk map using a systematic and practicable variable selection process for spatial analysis and mapping of historical malaria risk in Botswana. Results Of 50 potential explanatory variables from eight environmental data themes, 42 were significantly associated with malaria prevalence in univariate logistic regression and were ranked by the Akaike Information Criterion. Those correlated with higher-ranking relatives of the same environmental theme, were temporarily excluded. The remaining 14 candidates were ranked by selection frequency after running automated step-wise selection procedures on 1000 bootstrap samples drawn from the data. A non-spatial multiple-variable model was developed through step-wise inclusion in order of selection frequency. Previously excluded variables were then re-evaluated for inclusion, using further step-wise bootstrap procedures, resulting in the exclusion of another variable. Finally a Bayesian geo-statistical model using Markov Chain Monte Carlo simulation was fitted to the data, resulting in a final model of three predictor variables, namely summer rainfall, mean annual temperature and altitude. Each was independently and significantly associated with malaria prevalence after allowing for spatial correlation. This model was used to predict malaria prevalence at unobserved locations, producing a smooth risk map for the whole country. Conclusion We have

Falls and fractures in participants and excluded non-participants of a fall prevention exercise program for elderly women with a history of falls: 1-year follow-up study.

Science.gov (United States)

Kim, Hunkyung; Yoshida, Hideyo; Suzuki, Takao

2014-04-01

To evaluate the effectiveness of a strength and balance enhancing exercise intervention as a means of preventing falls in community-dwelling elderly Japanese women with a history of falls, while comparing functional fitness, fall and fracture rate in excluded subjects. A 1-year follow-up trial was carried out on 105 participants over the age of 70 years, who were randomly assigned to the exercise or education group, and also on 91 women excluded based on the exclusion criteria. The exercise group attended a 60-min exercise class twice a week for 3 months. Falls, injuries, fractures, and functional fitness assessments were measured at baseline, post-intervention and 1-year follow up. During the follow up, fall rates were 19.6% in the exercise group, 40.4% in the education group and 40.8% in excluded subjects (χ(2)  = 7.069, P = 0.029). Compared with the exercise group, the odds ratio (OR) for falls was greater in the education group (OR 2.78, 95% confidence interval (CI) 1.17-6.96) and excluded participants (OR 2.83, 95%CI 1.25-6.80). The OR for fractures was over fourfold greater in excluded participants (OR 4.30, 95% CI 1.02-9.70) than the exercise group. The exercise intervention for participants with fall history effectively decreased incidences of falls and fractures. However, fall and fracture rates in excluded people were high. Further research focusing on feasible countermeasures for falls in excluded people who are at high risk of fractures is required. © 2013 Japan Geriatrics Society.

When non-Gaussian states are Gaussian: Generalization of nonseparability criterion for continuous variables

International Nuclear Information System (INIS)

McHugh, Derek; Buzek, Vladimir; Ziman, Mario

2006-01-01

We present a class of non-Gaussian two-mode continuous-variable states for which the separability criterion for Gaussian states can be employed to detect whether they are separable or not. These states reduce to the two-mode Gaussian states as a special case

26 CFR 31.3402(e)-1 - Included and excluded wages.

Science.gov (United States)

2010-04-01

... 26 Internal Revenue 15 2010-04-01 2010-04-01 false Included and excluded wages. 31.3402(e)-1... SOURCE Collection of Income Tax at Source § 31.3402(e)-1 Included and excluded wages. (a) If a portion of... not more than 31 consecutive days constitutes wages, and the remainder does not constitute wages, all...

Expression of Toll-like receptor 9 and response to bacterial CpG oligodeoxynucleotides in human intestinal epithelium

DEFF Research Database (Denmark)

Pedersen, G; Andresen, Lars; Matthiessen, M W

2005-01-01

Recognition of repeat CpG motifs, which are common in bacterial, but not in mammalian, DNA, through Toll-like receptor (TLR)9 is an integral part of the innate immune system. As the role of TLR9 in the human gut is unknown, we determined the spectrum of TLR9 expression in normal and inflamed colo...... in vitro despite spontaneous TLR9 gene expression. This suggests that the human epithelium is able to avoid inappropriate immune responses to luminal bacterial products through modulation of the TLR9 pathway....

Dyslexic adults can learn from repeated stimulus presentation but have difficulties in excluding external noise.

Directory of Open Access Journals (Sweden)

Rachel L Beattie

Full Text Available We examined whether the characteristic impairments of dyslexia are due to a deficit in excluding external noise or a deficit in taking advantage of repeated stimulus presentation. We compared non-impaired adults and adults with poor reading performance on a visual letter detection task that varied two aspects: the presence or absence of background visual noise, and a small or large stimulus set. There was no interaction between group and stimulus set size, indicating that the poor readers took advantage of repeated stimulus presentation as well as the non-impaired readers. The poor readers had higher thresholds than non-impaired readers in the presence of high external noise, but not in the absence of external noise. The results support the hypothesis that an external noise exclusion deficit, not a perceptual anchoring deficit, impairs reading for adults.

Variability of pesticide exposure in a stream mesocosm system: Macrophyte-dominated vs. non-vegetated sections

Energy Technology Data Exchange (ETDEWEB)

Beketov, Mikhail A. [UFZ - Helmholtz Centre for Environmental Research, Department of System Ecotoxicology, Permoserstrasse 15, D-04318 Leipzig (Germany)], E-mail: mikhail.beketov@ufz.de; Liess, Matthias [UFZ - Helmholtz Centre for Environmental Research, Department of System Ecotoxicology, Permoserstrasse 15, D-04318 Leipzig (Germany)

2008-12-15

For flowing water bodies no information is available about patterns of contaminant distribution in flowing water compared to macrophyte-dominated structures. The aim of the study was to examine temporal dynamic and spatial cross-channel variability of pulse exposure of the insecticide thiacloprid in outdoor stream mesocosms. Two distinct cross-channel sections have been considered: macrophyte-dominated littoral and non-vegetated midstream. Median disappearance time ranged from 17 to 43 h (water phase, midstream). We showed that during the exposure pulse (10 h) thiacloprid concentrations in the macrophyte-dominated section were 20-60% lower than those in the non-vegetated section. This suggests that spatial variability in contaminant concentrations, particularly in streams containing macrophytes, should be taken into account to enable a more realistic assessment of (i) exposure and associated effects and (ii) mass transport of pesticides and other chemicals into river systems (e.g. losses with surface runoff). - Spatial cross-channel variability of contaminant concentrations is noteworthy and important.

Variability of pesticide exposure in a stream mesocosm system: Macrophyte-dominated vs. non-vegetated sections

International Nuclear Information System (INIS)

Beketov, Mikhail A.; Liess, Matthias

2008-01-01

For flowing water bodies no information is available about patterns of contaminant distribution in flowing water compared to macrophyte-dominated structures. The aim of the study was to examine temporal dynamic and spatial cross-channel variability of pulse exposure of the insecticide thiacloprid in outdoor stream mesocosms. Two distinct cross-channel sections have been considered: macrophyte-dominated littoral and non-vegetated midstream. Median disappearance time ranged from 17 to 43 h (water phase, midstream). We showed that during the exposure pulse (10 h) thiacloprid concentrations in the macrophyte-dominated section were 20-60% lower than those in the non-vegetated section. This suggests that spatial variability in contaminant concentrations, particularly in streams containing macrophytes, should be taken into account to enable a more realistic assessment of (i) exposure and associated effects and (ii) mass transport of pesticides and other chemicals into river systems (e.g. losses with surface runoff). - Spatial cross-channel variability of contaminant concentrations is noteworthy and important

The pathophysiology of the aqueduct stroke volume in normal pressure hydrocephalus: can co-morbidity with other forms of dementia be excluded?

International Nuclear Information System (INIS)

Bateman, Grant A.; Levi, Christopher R.; Wang, Yang; Lovett, Elizabeth C.; Schofield, Peter

2005-01-01

Variable results are obtained from the treatment of normal pressure hydrocephalus (NPH) by shunt insertion. There is a high correlation between NPH and the pathology of Alzheimer's disease (AD) on brain biopsy. There is an overlap between AD and vascular dementia (VaD), suggesting that a correlation exists between NPH and other forms of dementia. This study seeks to (1) understand the physiological factors behind, and (2) define the ability of, the aqueduct stroke volume to exclude dementia co-morbidity. Twenty-four patients from a dementia clinic were classified as having either early AD or VaD on the basis of clinical features, Hachinski score and neuropsychological testing. They were compared with 16 subjects with classical clinical findings of NPH and 12 aged-matched non-cognitively impaired subjects. MRI flow quantification was used to measure aqueduct stroke volume and arterial pulse volume. An arterio-cerebral compliance ratio was calculated from the two volumes in each patient. The aqueduct stroke volume was elevated in all three forms of dementia, with no significant difference noted between the groups. The arterial pulse volume was elevated by 24% in VaD and reduced by 35% in NPH, compared to normal (P=0.05 and P=0.002, respectively), and was normal in AD. There was a spectrum of relative compliance with normal compliance in VaD and reduced compliance in AD and NPH. The aqueduct stroke volume depends on the arterial pulse volume and the relative compliance between the arterial tree and brain. The aqueduct stroke volume cannot exclude significant co-morbidity in NPH. (orig.)

The pathophysiology of the aqueduct stroke volume in normal pressure hydrocephalus: can co-morbidity with other forms of dementia be excluded?

Energy Technology Data Exchange (ETDEWEB)

Bateman, Grant A. [John Hunter Hospital, Department of Medical Imaging, Newcastle (Australia); Levi, Christopher R.; Wang, Yang; Lovett, Elizabeth C. [Hunter Medical Research Institute, Clinical Neurosciences Program, Newcastle (Australia); Schofield, Peter [James Fletcher Hospital, Neuropsychiatry Unit, Newcastle (Australia)

2005-10-01

Variable results are obtained from the treatment of normal pressure hydrocephalus (NPH) by shunt insertion. There is a high correlation between NPH and the pathology of Alzheimer's disease (AD) on brain biopsy. There is an overlap between AD and vascular dementia (VaD), suggesting that a correlation exists between NPH and other forms of dementia. This study seeks to (1) understand the physiological factors behind, and (2) define the ability of, the aqueduct stroke volume to exclude dementia co-morbidity. Twenty-four patients from a dementia clinic were classified as having either early AD or VaD on the basis of clinical features, Hachinski score and neuropsychological testing. They were compared with 16 subjects with classical clinical findings of NPH and 12 aged-matched non-cognitively impaired subjects. MRI flow quantification was used to measure aqueduct stroke volume and arterial pulse volume. An arterio-cerebral compliance ratio was calculated from the two volumes in each patient. The aqueduct stroke volume was elevated in all three forms of dementia, with no significant difference noted between the groups. The arterial pulse volume was elevated by 24% in VaD and reduced by 35% in NPH, compared to normal (P=0.05 and P=0.002, respectively), and was normal in AD. There was a spectrum of relative compliance with normal compliance in VaD and reduced compliance in AD and NPH. The aqueduct stroke volume depends on the arterial pulse volume and the relative compliance between the arterial tree and brain. The aqueduct stroke volume cannot exclude significant co-morbidity in NPH. (orig.)

Non-Markovian dynamics, decoherence and entanglement in dissipative quantum systems with applications to quantum information theory of continuous variable systems

International Nuclear Information System (INIS)

Hoerhammer, C.

2007-01-01

In this thesis, non-Markovian dynamics, decoherence and entanglement in dissipative quantum systems are studied. In particular, applications to quantum information theory of continuous variable systems are considered. The non-Markovian dynamics are described by the Hu-Paz-Zhang master equation of quantum Brownian motion. In this context the focus is on non-Markovian effects on decoherence and separability time scales of various single- mode and two-mode continuous variable states. It is verified that moderate non-Markovian influences slow down the decay of interference fringes and quantum correlations, while strong non-Markovian effects resulting from an out-of-resonance bath can even accelerate the loss of coherence, compared to predictions of Markovian approximations. Qualitatively different scenarios including exponential, Gaussian or algebraic decay of the decoherence function are analyzed. It is shown that partial recurrence of coherence can occur in case of non-Lindblad-type dynamics. The time evolution of quantum correlations of entangled two-mode continuous variable states is examined in single-reservoir and two-reservoir models, representing noisy correlated or uncorrelated non-Markovian quantum channels. For this purpose the model of quantum Brownian motion is extended. Various separability criteria for Gaussian and non-Gaussian continuous variable systems are applied. In both types of reservoir models moderate non-Markovian effects prolong the separability time scales. However, in these models the properties of the stationary state may differ. In the two-reservoir model the initial entanglement is completely lost and both modes are finally uncorrelated. In a common reservoir both modes interact indirectly via the coupling to the same bath variables. Therefore, new quantum correlations may emerge between the two modes. Below a critical bath temperature entanglement is preserved even in the steady state. A separability criterion is derived, which depends

Locality or non-locality in quantum mechanics: hidden variables without ''spooky action-at-a-distance''

International Nuclear Information System (INIS)

Aharonov, Y.; Scully, M.

2001-01-01

The folklore notion of the ''Non-Locality of Quantum Mechanics'' is examined from the point of view of hidden-variables theories according to Belinfante's classification in his Survey of Hidden Variables Theories. It is here shown that in the case of EPR, there exist hidden variables theories that successfully reproduce quantum-mechanical predictions, but which are explicitly local. Since such theories do not fall into Belinfante's classification, we propose an expanded classification which includes similar theories, which we term as theories of the ''third'' kind. Causal implications of such theories are explored. (orig.)

No association of CpG island methylator phenotype and colorectal cancer survival: population-based study.

Science.gov (United States)

Jia, Min; Jansen, Lina; Walter, Viola; Tagscherer, Katrin; Roth, Wilfried; Herpel, Esther; Kloor, Matthias; Bläker, Hendrik; Chang-Claude, Jenny; Brenner, Hermann; Hoffmeister, Michael

2016-11-22

Previous studies have shown adverse effects of CpG island methylator phenotype (CIMP) on colorectal cancer (CRC) prognosis. However, sample sizes were often limited and only few studies were able to adjust for relevant molecular features associated with CIMP. The aim of this study was to investigate the impact of CIMP on CRC survival in a large population-based study with comprehensive adjustment. The CIMP status and other molecular tumour features were analysed in 1385 CRC patients diagnosed between 2003 and 2010. Detailed information were obtained from standardised personal interviews and medical records. During follow-up (median: 4.9 years), we assessed vital status, cause of death and therapy details. Cox proportional hazard regression models were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of survival after CRC. The CIMP-H occurred more frequently in patients with older age, female gender, cancer in the proximal colon, BRAF mutation and microsatellite instability-high (MSI-H). However, CIMP status was not associated with CRC prognosis in CRC patients (HR=1.00; 95% CI=0.72-1.40 for overall survival; HR=0.96; 95% CI=0.65-1.41 for disease-specific survival) or in any of the subgroups. Although CIMP status was associated with the presence of MSI-H and BRAF mutation, the prognostic effects of MSI-H (HR=0.49; 95% CI=0.27-0.90) and BRAF mutation (HR=1.78; 95% CI=1.10-2.84) were independent of CIMP status. Similar benefit of chemotherapy was found for CRC outcomes in both the CIMP-low/negative group and the CIMP-high group. CpG island methylator phenotype was not associated with CRC prognosis after adjusting for other important clinical factors and associated mutations.

CpG in Combination with an Inhibitor of Notch Signaling Suppresses Formalin-Inactivated Respiratory Syncytial Virus-Enhanced Airway Hyperresponsiveness and Inflammation by Inhibiting Th17 Memory Responses and Promoting Tissue-Resident Memory Cells in Lungs.

Science.gov (United States)

Zhang, Lei; Li, Hongyong; Hai, Yan; Yin, Wei; Li, Wenjian; Zheng, Boyang; Du, Xiaomin; Li, Na; Zhang, Zhengzheng; Deng, Yuqing; Zeng, Ruihong; Wei, Lin

2017-05-15

Respiratory syncytial virus (RSV) is the leading cause of childhood hospitalizations. The formalin-inactivated RSV (FI-RSV) vaccine-enhanced respiratory disease (ERD) has been an obstacle to the development of a safe and effective killed RSV vaccine. Agonists of Toll-like receptor (TLR) have been shown to regulate immune responses induced by FI-RSV. Notch signaling plays critical roles during the differentiation and effector function phases of innate and adaptive immune responses. Cross talk between TLR and Notch signaling pathways results in fine-tuning of TLR-triggered innate inflammatory responses. We evaluated the impact of TLR and Notch signaling on ERD in a murine model by administering CpG, an agonist of TLR9, in combination with L685,458, an inhibitor of Notch signaling during FI-RSV immunization. Activation with CpG or deficiency of MyD88-dependent TLR signaling did not alleviate airway inflammation in FI-RSV-immunized mice. Activation or inhibition of Notch signaling with Dll4, one of the Notch ligands, or L685,458 did not suppress FI-RSV-enhanced airway inflammation either. However, the CpG together with L685,458 markedly inhibited FI-RSV-enhanced airway hyperresponsiveness, weight loss, and lung inflammation. Interestingly, CpG plus L685,458 completely inhibited FI-RSV-associated Th17 and Th17-associated proinflammatory chemokine responses in lungs following RSV challenge but not Th1 or Th2, memory responses. In addition, FI-RSV plus CpG plus L685,458 promoted protective CD8 + lung tissue-resident memory (TRM) cells. These results indicate that activation of TLR signaling combined with inhibition of Notch signaling prevent FI-RSV ERD, and the mechanism appears to involve suppressing proinflammatory Th17 memory responses and promoting protective TRM in lungs. IMPORTANCE RSV is the most important cause of lower respiratory tract infections in infants. The FI-RSV-enhanced respiratory disease (ERD) is a major impediment to the development of a safe and

GUILT OF PERSONS WITH MENTAL DISORDERS ARE NOT EXCLUDING RESPONSIBILITIES

Directory of Open Access Journals (Sweden)

Ekaterina Valerievna Yurchak

2014-10-01

Full Text Available In the theory of law as a key cross-sectoral and multi-disciplinary institutions is the Institute of guilt. At the present stage of development of the law, in a convergence of many of its branches, it is important to investigate exhaustively the institution with the general legal position, both in general and in particular - the situation of the guilt of persons with mental disorder, not excluding sanity.The purpose of this study - to investigate the situation of the fault of persons with a mental disorder, not excluding sanity in different areas of law, and address the question of whether this interdisciplinary institute.Scientific, theoretical and practical significance of the work lies in the fact that the study of this topic will summarize the knowledge about the fault of persons with a mental disorder, not excluding sanity, to analyze the content of this institution in various areas of law, and to conclude that the cross-sectoral character.The author uses formal-legal, comparative, hermeneutical, mathematical methods, as well as general methods of scientific research.The author analyzes the provisions of the Russian legislation on the fault of persons with a mental disorder, not excluding sanity, concluding that the criminal law of guilt people with a mental disorder, not excluding sanity, the most developed and taken into account as a circumstance affecting the punishment. In other areas of the law said institution worked shallow.The results of this study are scientific and practical value, because they can be useful for teaching students - in the industrial discipline "Criminal Law" and the general theoretical discipline "Theory of State and Law"; in science - by picking up information about the features of the Institute of guilt, and in practice - said the work can be useful to practitioners of judicial and investigative bodies, in order to understand the meaning and importance of the category of guilt, including - the guilt of persons

17 CFR 37.4 - Election to trade excluded and exempt commodities.

Science.gov (United States)

2010-04-01

... 17 Commodity and Securities Exchanges 1 2010-04-01 2010-04-01 false Election to trade excluded and exempt commodities. 37.4 Section 37.4 Commodity and Securities Exchanges COMMODITY FUTURES TRADING COMMISSION DERIVATIVES TRANSACTION EXECUTION FACILITIES § 37.4 Election to trade excluded and exempt...

Preferences for travel time variability – A study of Danish car drivers

DEFF Research Database (Denmark)

Hjorth, Katrine; Rich, Jeppe

Travel time variability (TTV) is a measure of the extent of unpredictability in travel times. It is generally accepted that TTV has a negative effect on travellers’ wellbeing and overall utility of travelling, and valuation of variability is an important issue in transport demand modelling...... preferences, to exclude non-traders, and to avoid complicated issues related to scheduled public transport services. The survey uses customised Internet questionnaires, containing a series of questions related to the traveller’s most recent morning trip to work, e.g.: • Travel time experienced on this day......, • Number of stops along the way, their duration, and whether these stops involved restrictions on time of day, • Restrictions regarding departure time from home or arrival time at work, • How often such a trip was made within the last month and the range of experienced travel times, • What the traveller...

Our grandmothers, excluded from history, preservers and ...

African Journals Online (AJOL)

Our grandmothers, excluded from history, preservers and transmitters of indegenous values: ecomaternalistic approach. ... Journal of Religion and Human Relations ... It further calls for the retrieval of the said hidden histories of women which would hopefully be a lesson for the contemporary and future women.

Investigating Einstein-Podolsky-Rosen steering of continuous-variable bipartite states by non-Gaussian pseudospin measurements

Science.gov (United States)

Xiang, Yu; Xu, Buqing; Mišta, Ladislav; Tufarelli, Tommaso; He, Qiongyi; Adesso, Gerardo

2017-10-01

Einstein-Podolsky-Rosen (EPR) steering is an asymmetric form of correlations which is intermediate between quantum entanglement and Bell nonlocality, and can be exploited as a resource for quantum communication with one untrusted party. In particular, steering of continuous-variable Gaussian states has been extensively studied theoretically and experimentally, as a fundamental manifestation of the EPR paradox. While most of these studies focused on quadrature measurements for steering detection, two recent works revealed that there exist Gaussian states which are only steerable by suitable non-Gaussian measurements. In this paper we perform a systematic investigation of EPR steering of bipartite Gaussian states by pseudospin measurements, complementing and extending previous findings. We first derive the density-matrix elements of two-mode squeezed thermal Gaussian states in the Fock basis, which may be of independent interest. We then use such a representation to investigate steering of these states as detected by a simple nonlinear criterion, based on second moments of the correlation matrix constructed from pseudospin operators. This analysis reveals previously unexplored regimes where non-Gaussian measurements are shown to be more effective than Gaussian ones to witness steering of Gaussian states in the presence of local noise. We further consider an alternative set of pseudospin observables, whose expectation value can be expressed more compactly in terms of Wigner functions for all two-mode Gaussian states. However, according to the adopted criterion, these observables are found to be always less sensitive than conventional Gaussian observables for steering detection. Finally, we investigate continuous-variable Werner states, which are non-Gaussian mixtures of Gaussian states, and find that pseudospin measurements are always more effective than Gaussian ones to reveal their steerability. Our results provide useful insights on the role of non

45 CFR 2400.63 - Excluded graduate study.

Science.gov (United States)

2010-10-01

... arts in public affairs or public administration. The Foundation may at its discretion, upon request of... 45 Public Welfare 4 2010-10-01 2010-10-01 false Excluded graduate study. 2400.63 Section 2400.63 Public Welfare Regulations Relating to Public Welfare (Continued) JAMES MADISON MEMORIAL FELLOWSHIP...

Use of resting myocardial scintigraphy during chest pain to exclude diagnosis of acute myocardial infarction

International Nuclear Information System (INIS)

Barbirato, Gustavo Borges; Azevedo, Jader Cunha de; Felix, Renata Christian Martins; Correa, Patricia Lavatori; Volschan, Andre; Viegas, Monica; Pimenta, Lucia; Dohmann, Hans Fernando Rocha; Mesquita, Evandro Tinoco; Mesquita, Claudio Tinoco

2009-01-01

Background: Images of myocardial perfusion taken during an episode of chest pain have been used for patients in the emergency department. Objective: To evaluate the operating characteristics of 99m Tc-Tetrofosmin scintigraphy during an episode of chest pain to exclude the diagnosis of cute myocardial infarction. Methods: One hundred and eight patients admitted with chest pain, or up to four hours after the end of symptoms and non diagnostic electrocardiogram, underwent resting scintigraphy and measurement of troponin I concentrations. Patients with a history of myocardial infarction (MI) were not excluded (24 patients). Troponin I concentrations were determined at admission and 6 hours later. Nuclear physicians performed a blind analysis of the images, and myocardial infarction was confirmed whenever troponin I level increase was three times that of the control. Results: Resting perfusion image was abnormal in all 6 patients with MI. Only 1 patient had a normal image and increased troponin levels. Fifty-five patients had positive images without MI, and 46 patients had normal images and troponin levels. The prevalence of the disease was 6.5%. The sensitivity and specificity of the resting images during an episode of chest pain to diagnose MI was 85.7% and 45.5%, respectively. The negative predictive value was 97.7%. Conclusion: Patients undergoing chest pain protocol with SPECT showed an excellent negative predictive value to exclude diagnosis of myocardial infarction. These results suggest that resting perfusion image is an important tool at the chest pain unit. (author)

Analysis of RET promoter CpG island methylation using methylation-specific PCR (MSP), pyrosequencing, and methylation-sensitive high-resolution melting (MS-HRM): impact on stage II colon cancer patient outcome.

Science.gov (United States)

Draht, Muriel X G; Smits, Kim M; Jooste, Valérie; Tournier, Benjamin; Vervoort, Martijn; Ramaekers, Chantal; Chapusot, Caroline; Weijenberg, Matty P; van Engeland, Manon; Melotte, Veerle

2016-01-01

Already since the 1990s, promoter CpG island methylation markers have been considered promising diagnostic, prognostic, and predictive cancer biomarkers. However, so far, only a limited number of DNA methylation markers have been introduced into clinical practice. One reason why the vast majority of methylation markers do not translate into clinical applications is lack of independent validation of methylation markers, often caused by differences in methylation analysis techniques. We recently described RET promoter CpG island methylation as a potential prognostic marker in stage II colorectal cancer (CRC) patients of two independent series. In the current study, we analyzed the RET promoter CpG island methylation of 241 stage II colon cancer patients by direct methylation-specific PCR (MSP), nested-MSP, pyrosequencing, and methylation-sensitive high-resolution melting (MS-HRM). All primers were designed as close as possible to the same genomic region. In order to investigate the effect of different DNA methylation assays on patient outcome, we assessed the clinical sensitivity and specificity as well as the association of RET methylation with overall survival for three and five years of follow-up. Using direct-MSP and nested-MSP, 12.0 % (25/209) and 29.6 % (71/240) of the patients showed RET promoter CpG island methylation. Methylation frequencies detected by pyrosequencing were related to the threshold for positivity that defined RET methylation. Methylation frequencies obtained by pyrosequencing (threshold for positivity at 20 %) and MS-HRM were 13.3 % (32/240) and 13.8 % (33/239), respectively. The pyrosequencing threshold for positivity of 20 % showed the best correlation with MS-HRM and direct-MSP results. Nested-MSP detected RET promoter CpG island methylation in deceased patients with a higher sensitivity (33.1 %) compared to direct-MSP (10.7 %), pyrosequencing (14.4 %), and MS-HRM (15.4 %). While RET methylation frequencies detected by nested

Non-linear variability in geophysics scaling and fractals

CERN Document Server

Lovejoy, S

1991-01-01

consequences of broken symmetry -here parity-is studied. In this model, turbulence is dominated by a hierarchy of helical (corkscrew) structures. The authors stress the unique features of such pseudo-scalar cascades as well as the extreme nature of the resulting (intermittent) fluctuations. Intermittent turbulent cascades was also the theme of a paper by us in which we show that universality classes exist for continuous cascades (in which an infinite number of cascade steps occur over a finite range of scales). This result is the multiplicative analogue of the familiar central limit theorem for the addition of random variables. Finally, an interesting paper by Pasmanter investigates the scaling associated with anomolous diffusion in a chaotic tidal basin model involving a small number of degrees of freedom. Although the statistical literature is replete with techniques for dealing with those random processes characterized by both exponentially decaying (non-scaling) autocorrelations and exponentially decaying...

48 CFR 52.247-7 - Freight Excluded.

Science.gov (United States)

2010-10-01

... 48 Federal Acquisition Regulations System 2 2010-10-01 2010-10-01 false Freight Excluded. 52.247-7... AND FORMS SOLICITATION PROVISIONS AND CONTRACT CLAUSES Text of Provisions and Clauses 52.247-7 Freight... contracts for transportation or for transportation-related services when any commodities or types of...

Excluded-volume effects in the diffusion of hard spheres

KAUST Repository

Bruna, Maria

2012-01-03

Excluded-volume effects can play an important role in determining transport properties in diffusion of particles. Here, the diffusion of finite-sized hard-core interacting particles in two or three dimensions is considered systematically using the method of matched asymptotic expansions. The result is a nonlinear diffusion equation for the one-particle distribution function, with excluded-volume effects enhancing the overall collective diffusion rate. An expression for the effective (collective) diffusion coefficient is obtained. Stochastic simulations of the full particle system are shown to compare well with the solution of this equation for two examples. © 2012 American Physical Society.

Clinical practice guidelines (CPGs) reduce costs in the management of isolated splenic injuries at pediatric trauma centers.

Science.gov (United States)

Gutierrez, Ivan M; Zurakowski, David; Chen, Qiaoli; Mooney, David P

2013-02-01

The American Pediatric Surgical Association Trauma Committee proposed the use of a clinical practice guideline (CPG) for the non-operative management of isolated splenic injuries in 1998. An analysis was conducted to determine the financial impact of CPGs on the management of these injuries. The Pediatric Health Information System database, which contains data from 44 children's hospitals, was used to identify children who sustained a graded isolated splenic injury between June 2005 and June 2010. Demographics, length of stay (LOS), readmission rates, and laboratory, imaging, procedural, and total cost data were determined for all hospitals verified as a pediatric trauma center by the American College of Surgeons and/or designated by their local authority. Comparisons were made between facilities self-identifying as having a splenic injury management CPG and those without a CPG. Children (1,154) with isolated splenic injuries (grades 1-4) were cared for in 26 pediatric trauma centers: 20 with a CPG and 6 without (non-CPG). Median costs were significantly lower at CPG than non-CPG centers for imaging (US $163 vs. US $641, P splenic injuries at a pediatric trauma center results in significantly reduced imaging, laboratory, and total hospital costs independent of patient age, gender, grade, and LOS.

21 CFR 1.362 - What records are excluded from this subpart?

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 1 2010-04-01 2010-04-01 false What records are excluded from this subpart? 1.362 Section 1.362 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL... Requirements § 1.362 What records are excluded from this subpart? The establishment and maintenance of records...

Changes in the Coding and Non-coding Transcriptome and DNA Methylome that Define the Schwann Cell Repair Phenotype after Nerve Injury.

Science.gov (United States)

Arthur-Farraj, Peter J; Morgan, Claire C; Adamowicz, Martyna; Gomez-Sanchez, Jose A; Fazal, Shaline V; Beucher, Anthony; Razzaghi, Bonnie; Mirsky, Rhona; Jessen, Kristjan R; Aitman, Timothy J

2017-09-12

Repair Schwann cells play a critical role in orchestrating nerve repair after injury, but the cellular and molecular processes that generate them are poorly understood. Here, we perform a combined whole-genome, coding and non-coding RNA and CpG methylation study following nerve injury. We show that genes involved in the epithelial-mesenchymal transition are enriched in repair cells, and we identify several long non-coding RNAs in Schwann cells. We demonstrate that the AP-1 transcription factor C-JUN regulates the expression of certain micro RNAs in repair Schwann cells, in particular miR-21 and miR-34. Surprisingly, unlike during development, changes in CpG methylation are limited in injury, restricted to specific locations, such as enhancer regions of Schwann cell-specific genes (e.g., Nedd4l), and close to local enrichment of AP-1 motifs. These genetic and epigenomic changes broaden our mechanistic understanding of the formation of repair Schwann cell during peripheral nervous system tissue repair. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

State-of-the-art sensor technology in Spain: invasive and non-invasive techniques for monitoring respiratory variables.

Science.gov (United States)

Domingo, Christian; Blanch, Lluis; Murias, Gaston; Luján, Manel

2010-01-01

The interest in measuring physiological parameters (especially arterial blood gases) has grown progressively in parallel to the development of new technologies. Physiological parameters were first measured invasively and at discrete time points; however, it was clearly desirable to measure them continuously and non-invasively. The development of intensive care units promoted the use of ventilators via oral intubation ventilators via oral intubation and mechanical respiratory variables were progressively studied. Later, the knowledge gained in the hospital was applied to out-of-hospital management. In the present paper we review the invasive and non-invasive techniques for monitoring respiratory variables.

20 CFR 404.1013 - Included-excluded rule.

Science.gov (United States)

2010-04-01

... least one-half of your time in the pay period is in covered work. If you spend most of your time in a... 20 Employees' Benefits 2 2010-04-01 2010-04-01 false Included-excluded rule. 404.1013 Section 404.1013 Employees' Benefits SOCIAL SECURITY ADMINISTRATION FEDERAL OLD-AGE, SURVIVORS AND DISABILITY...

Caspase 8 and maspin are downregulated in breast cancer cells due to CpG site promoter methylation

International Nuclear Information System (INIS)

Wu, Yanyuan; Alvarez, Monica; Slamon, Dennis J; Koeffler, Phillip; Vadgama, Jaydutt V

2010-01-01

Epigenetic changes associated with promoter DNA methylation results in silencing of several tumor suppressor genes that lead to increased risk for tumor formation and for progression of the cancer. Methylation specific PCR (MSP) and bisulfite sequencing were used for determination of proapoptotic gene Caspase 8 (CASP8) and the tumor suppressor gene maspin promoter methylation in four breast cancer and two non-tumorigenic breast cell lines. Involvement of histone H3 methylation in those cell lines were examined by CHIP assay. The CpG sites in the promoter region of CASP8 and maspin were methylated in all four breast cancer cell lines but not in two non-tumorigenic breast cell lines. Demethylation agent 5-aza-2'-deoxycytidine (5-aza-dc) selectively inhibits DNA methyltransferases, DNMT3a and DNMT3b, and restored CASP8 and maspin gene expression in breast cancer cells. 5-aza-dc also reduced histone H3k9me2 occupancy on CASP8 promoter in SKBR3cells, but not in MCF-7 cells. Combination of histone deacetylase inhibitor Trichostatin A (TSA) and 5-aza-dc significant decrease in nuclear expression of Di-methyl histone H3-Lys27 and slight increase in acetyl histone H3-Lys9 in MCF-7 cells. CASP8 mRNA and protein level in MCF-7 cells were increased by the 5-aza-dc in combination with TSA. Data from our study also demonstrated that treatment with 5-FU caused a significant increase in unmethylated CASP8 and in CASP8 mRNA in all 3 cancer lines. CASP8 and maspin expression were reduced in breast cancer cells due to promoter methylation. Selective application of demethylating agents could offer novel therapeutic opportunities in breast cancer

Empowering the digitally excluded: learning initiatives for (invisible groups

Directory of Open Access Journals (Sweden)

Jane Seale

2012-12-01

Full Text Available There is growing evidence that some digitally excluded groups of learners are receiving more attention than others. Discussions regarding why some digitally excluded learners are more visible than others and therefore worthy of more committed digital inclusion interventions raises important questions about how we define and conceptualise digital inclusion and digital inclusion practice; particularly in relation to empowerment. In this article, we draw on a range of research, practice and policy literature to examine two important questions: what is empowerment and in whose hands does empowerment lie? We argue that empowerment involves making informed choices about technology use, but that learners often require support- human intervention- to make these choices. However, current digital inclusion research has failed to produce a detailed critique of what constitutes empowering support from educational institutions and their staff. A lack of open and reflexive accounts of practice means that we are no closer to identifying and understanding the kinds of empowering practices that are required to challenge the kinds of prejudices, stereotypes, risk-aversiveness and low aspirations associated with the most invisible of digitally excluded learners.

Clinical Significance of MLH1 Methylation and CpG Island Methylator Phenotype as Prognostic Markers in Patients with Gastric Cancer

Science.gov (United States)

Shigeyasu, Kunitoshi; Nagasaka, Takeshi; Mori, Yoshiko; Yokomichi, Naosuke; Kawai, Takashi; Fuji, Tomokazu; Kimura, Keisuke; Umeda, Yuzo; Kagawa, Shunsuke; Goel, Ajay; Fujiwara, Toshiyoshi

2015-01-01

Background To improve the outcome of patients suffering from gastric cancer, a better understanding of underlying genetic and epigenetic events in this malignancy is required. Although CpG island methylator phenotype (CIMP) and microsatellite instability (MSI) have been shown to play pivotal roles in gastric cancer pathogenesis, the clinical significance of these events on survival outcomes in patients with gastric cancer remains unknown. Methods This study included a patient cohort with pathologically confirmed gastric cancer who had surgical resections. A cohort of 68 gastric cancers was analyzed. CIMP and MSI statuses were determined by analyzing promoter CpG island methylation status of 28 genes/loci, and genomic instability at 10 microsatellite markers, respectively. A Cox’s proportional hazards model was performed for multivariate analysis including age, stage, tumor differentiation, KRAS mutation status, and combined CIMP/MLH1 methylation status in relation to overall survival (OS). Results By multivariate analysis, longer OS was significantly correlated with lower pathologic stage (P = 0.0088), better tumor differentiation (P = 0.0267) and CIMP-high and MLH1 3' methylated status (P = 0.0312). Stratification of CIMP status with regards to MLH1 methylation status further enabled prediction of gastric cancer prognosis. Conclusions CIMP and/or MLH1 methylation status may have a potential to be prognostic biomarkers for patients with gastric cancer. PMID:26121593

Clinical Significance of MLH1 Methylation and CpG Island Methylator Phenotype as Prognostic Markers in Patients with Gastric Cancer.

Directory of Open Access Journals (Sweden)

Kunitoshi Shigeyasu

Full Text Available To improve the outcome of patients suffering from gastric cancer, a better understanding of underlying genetic and epigenetic events in this malignancy is required. Although CpG island methylator phenotype (CIMP and microsatellite instability (MSI have been shown to play pivotal roles in gastric cancer pathogenesis, the clinical significance of these events on survival outcomes in patients with gastric cancer remains unknown.This study included a patient cohort with pathologically confirmed gastric cancer who had surgical resections. A cohort of 68 gastric cancers was analyzed. CIMP and MSI statuses were determined by analyzing promoter CpG island methylation status of 28 genes/loci, and genomic instability at 10 microsatellite markers, respectively. A Cox's proportional hazards model was performed for multivariate analysis including age, stage, tumor differentiation, KRAS mutation status, and combined CIMP/MLH1 methylation status in relation to overall survival (OS.By multivariate analysis, longer OS was significantly correlated with lower pathologic stage (P = 0.0088, better tumor differentiation (P = 0.0267 and CIMP-high and MLH1 3' methylated status (P = 0.0312. Stratification of CIMP status with regards to MLH1 methylation status further enabled prediction of gastric cancer prognosis.CIMP and/or MLH1 methylation status may have a potential to be prognostic biomarkers for patients with gastric cancer.

Metronomic Doses of Temozolomide Enhance the Efficacy of Carbon Nanotube CpG Immunotherapy in an Invasive Glioma Model.

Directory of Open Access Journals (Sweden)

Mao Ouyang

Full Text Available Even when treated with aggressive current therapies, most patients with glioblastoma survive less than two years. Rapid tumor growth, an invasive nature, and the blood-brain barrier, which limits the penetration of large molecules into the brain, all contribute to the poor tumor response associated with conventional therapies. Immunotherapy has emerged as a therapeutic approach that may overcome these challenges. We recently reported that single-walled carbon nanotubes (SWCNTs can be used to dramatically increase the immunotherapeutic efficacy of CpG oligonucleotides in a mouse model of glioma. Following implantation in the mouse brain, the tumor cell line used in these previous studies (GL261 tends to form a spherical tumor with limited invasion into healthy brain. In order to evaluate SWCNT/CpG therapy under more clinically-relevant conditions, here we report the treatment of a more invasive mouse glioma model (K-Luc that better recapitulates human disease. In addition, a CpG sequence previously tested in humans was used to formulate the SWCNT/CpG which was combined with temozolomide, the standard of care chemotherapy for glioblastoma patients. We found that, following two intracranial administrations, SWCNT/CpG is well-tolerated and improves the survival of mice bearing invasive gliomas. Interestingly, the efficacy of SWCNT/CpG was enhanced when combined with temozolomide. This enhanced anti-tumor efficacy was correlated to an increase of tumor-specific cytotoxic activity in splenocytes. These results reinforce the emerging understanding that immunotherapy can be enhanced by combining it with chemotherapy and support the continued development of SWCNT/CpG.

Comparing Facebook Users and Facebook Non-Users: Relationship between Personality Traits and Mental Health Variables - An Exploratory Study.

Science.gov (United States)

Brailovskaia, Julia; Margraf, Jürgen

2016-01-01

Over one billion people use Facebook as a platform for social interaction and self-presentation making it one of the most popular online sites. The aim of the present study was to investigate differences in various personality traits and mental health variables between Facebook users and people who do not use this platform. The data of 945 participants (790 Facebook users, 155 Facebook non-users) were collected. Results indicate that Facebook users score significantly higher on narcissism, self-esteem and extraversion than Facebook non-users. Furthermore, they have significantly higher values of social support, life satisfaction and subjective happiness. Facebook non-users have (marginally) significantly higher values of depression symptoms than Facebook users. In both groups, extraversion, self-esteem, happiness, life satisfaction, resilience and social support, on the one hand, and depression, anxiety and stress symptoms, on the other hand, are negatively correlated. Neuroticism is positively associated with depression, anxiety and stress symptoms. However, significant differences exist between Facebook users and Facebook non-users regarding some associations of personality traits and mental health variables. Compared to Facebook non-users, the present results indicate that Facebook users have higher values of certain personality traits and positive variables protecting mental health. These findings are of particular interest considering the high importance of social online-platforms in the daily life of many people.

Comparing Facebook Users and Facebook Non-Users: Relationship between Personality Traits and Mental Health Variables - An Exploratory Study.

Directory of Open Access Journals (Sweden)

Julia Brailovskaia

Full Text Available Over one billion people use Facebook as a platform for social interaction and self-presentation making it one of the most popular online sites. The aim of the present study was to investigate differences in various personality traits and mental health variables between Facebook users and people who do not use this platform. The data of 945 participants (790 Facebook users, 155 Facebook non-users were collected. Results indicate that Facebook users score significantly higher on narcissism, self-esteem and extraversion than Facebook non-users. Furthermore, they have significantly higher values of social support, life satisfaction and subjective happiness. Facebook non-users have (marginally significantly higher values of depression symptoms than Facebook users. In both groups, extraversion, self-esteem, happiness, life satisfaction, resilience and social support, on the one hand, and depression, anxiety and stress symptoms, on the other hand, are negatively correlated. Neuroticism is positively associated with depression, anxiety and stress symptoms. However, significant differences exist between Facebook users and Facebook non-users regarding some associations of personality traits and mental health variables. Compared to Facebook non-users, the present results indicate that Facebook users have higher values of certain personality traits and positive variables protecting mental health. These findings are of particular interest considering the high importance of social online-platforms in the daily life of many people.

Heart Rate Variability and Wavelet-based Studies on ECG Signals from Smokers and Non-smokers

Science.gov (United States)

Pal, K.; Goel, R.; Champaty, B.; Samantray, S.; Tibarewala, D. N.

2013-12-01

The current study deals with the heart rate variability (HRV) and wavelet-based ECG signal analysis of smokers and non-smokers. The results of HRV indicated dominance towards the sympathetic nervous system activity in smokers. The heart rate was found to be higher in case of smokers as compared to non-smokers ( p smokers from the non-smokers. The results indicated that when RMSSD, SD1 and RR-mean features were used concurrently a classification efficiency of > 90 % was achieved. The wavelet decomposition of the ECG signal was done using the Daubechies (db 6) wavelet family. No difference was observed between the smokers and non-smokers which apparently suggested that smoking does not affect the conduction pathway of heart.

Coupled Effects of non-Newtonian Rheology and Aperture Variability on Flow in a Single Fracture

Science.gov (United States)

Di Federico, V.; Felisa, G.; Lauriola, I.; Longo, S.

2017-12-01

Modeling of non-Newtonian flow in fractured media is essential in hydraulic fracturing and drilling operations, EOR, environmental remediation, and to understand magma intrusions. An important step in the modeling effort is a detailed understanding of flow in a single fracture, as the fracture aperture is spatially variable. A large bibliography exists on Newtonian and non-Newtonian flow in variable aperture fractures. Ultimately, stochastic or deterministic modeling leads to the flowrate under a given pressure gradient as a function of the parameters describing the aperture variability and the fluid rheology. Typically, analytical or numerical studies are performed adopting a power-law (Oswald-de Waele) model. Yet the power-law model, routinely used e.g. for hydro-fracturing modeling, does not characterize real fluids at low and high shear rates. A more appropriate rheological model is provided by e.g. the four-parameter Carreau constitutive equation, which is in turn approximated by the more tractable truncated power-law model. Moreover, fluids of interest may exhibit yield stress, which requires the Bingham or Herschel-Bulkely model. This study employs different rheological models in the context of flow in variable aperture fractures, with the aim of understanding the coupled effect of rheology and aperture spatial variability with a simplified model. The aperture variation, modeled within a stochastic or deterministic framework, is taken to be one-dimensional and i) perpendicular; ii) parallel to the flow direction; for stochastic modeling, the influence of different distribution functions is examined. Results for the different rheological models are compared with those obtained for the pure power-law. The adoption of the latter model leads to overestimation of the flowrate, more so for large aperture variability. The presence of yield stress also induces significant changes in the resulting flowrate for assigned external pressure gradient.

Metastatic Ewing's sarcoma to the skull: CNS involvement excluded by MRI

International Nuclear Information System (INIS)

Taets ven Amerongen, A.H.M.; Kaiser, M.C.; Waal, F.C. de

1987-01-01

A case of metastatic Ewing's sarcoma to the skull is presented, demonstrating the superiority of magnetic resonance imaging over other imaging modalities to exclude CNS involvement. Precise delineation of different tumor components in extradural location contained in an intact dural rim together with compressed cortex showing no signs of tumorous involvement constituted an MRI appearance allowing us to exclude tumor outgrowth into the brain. (orig.)

A discrete fibre dispersion method for excluding fibres under compression in the modelling of fibrous tissues.

Science.gov (United States)

Li, Kewei; Ogden, Ray W; Holzapfel, Gerhard A

2018-01-01

Recently, micro-sphere-based methods derived from the angular integration approach have been used for excluding fibres under compression in the modelling of soft biological tissues. However, recent studies have revealed that many of the widely used numerical integration schemes over the unit sphere are inaccurate for large deformation problems even without excluding fibres under compression. Thus, in this study, we propose a discrete fibre dispersion model based on a systematic method for discretizing a unit hemisphere into a finite number of elementary areas, such as spherical triangles. Over each elementary area, we define a representative fibre direction and a discrete fibre density. Then, the strain energy of all the fibres distributed over each elementary area is approximated based on the deformation of the representative fibre direction weighted by the corresponding discrete fibre density. A summation of fibre contributions over all elementary areas then yields the resultant fibre strain energy. This treatment allows us to exclude fibres under compression in a discrete manner by evaluating the tension-compression status of the representative fibre directions only. We have implemented this model in a finite-element programme and illustrate it with three representative examples, including simple tension and simple shear of a unit cube, and non-homogeneous uniaxial extension of a rectangular strip. The results of all three examples are consistent and accurate compared with the previously developed continuous fibre dispersion model, and that is achieved with a substantial reduction of computational cost. © 2018 The Author(s).

Up-regulation of expression and lack of 5' CpG island hypermethylation of p16 INK4a in HPV-positive cervical carcinomas

International Nuclear Information System (INIS)

Ivanova, Tatiana A; Golovina, Daria A; Zavalishina, Larisa E; Volgareva, Galina M; Katargin, Alexey N; Andreeva, Yulia Y; Frank, Georgy A; Kisseljov, Fjodor L; Kisseljova, Natalia P

2007-01-01

High risk type human papilloma viruses (HR-HPV) induce carcinomas of the uterine cervix by expressing viral oncogenes E6 and E7. Oncogene E7 of HR-HPV disrupts the pRb/E2F interaction, which negatively regulates the S phase entry. Expression of tumor suppressor p16 ink4a drastically increases in majority of HR-HPV associated carcinomas due to removal of pRb repression. The p16 ink4a overexpression is an indicator of an aberrant expression of viral oncogenes and may serve as a marker for early diagnostic of cervical cancer. On the other hand, in 25–57% of cervical carcinomas hypermethylation of the p16 INK4a promoter has been demonstrated using a methylation-specific PCR, MSP. To evaluate a potential usage of the p16 INK4a 5' CpG island hypermethylation as an indicator of tumor cell along with p16 ink4a overexpression, we analyzed the methylation status of p16 INK4a in cervical carcinomas Methylation status of p16 INK4a was analyzed by MSP and by bisulfite-modified DNA sequencing. The expression of p16 ink4a was analyzed by RT-PCR and by immunohistochemical technique. The extensive methylation within p16 INK4a 5' CpG island was not detected either in 13 primary cervical carcinomas or in 5 cancer cell lines by bisulfite-modified DNA sequencing (including those that were positive by MSP in our hands). The number and distribution of rare partially methylated CpG sites did not differ considerably in tumors and adjacent normal tissues. The levels of the p16 INK4a mRNA were increased in carcinomas compared to the normal tissues independently of the number of partially methylated CpGs within 5'CpG island. The transcriptional activation of p16 INK4a was accompanied by p16 ink4a cytoplasmic immunoreactivity in the majority of tumor cells and presence of a varied number of the p16 positive nuclei in different tumors. Hypermethylaion of the p16INK4a 5' CpG island is not a frequent event in HR-HPV-positive cervical carcinomas and cannot be an effective

Being Included and Excluded

DEFF Research Database (Denmark)

Korzenevica, Marina

2016-01-01

Following the civil war of 1996–2006, there was a dramatic increase in the labor mobility of young men and the inclusion of young women in formal education, which led to the transformation of the political landscape of rural Nepal. Mobility and schooling represent a level of prestige that rural...... politics. It analyzes how formal education and mobility either challenge or reinforce traditional gendered norms which dictate a lowly position for young married women in the household and their absence from community politics. The article concludes that women are simultaneously excluded and included from...... community politics. On the one hand, their mobility and decision-making powers decrease with the increase in the labor mobility of men and their newly gained education is politically devalued when compared to the informal education that men gain through mobility, but on the other hand, schooling strengthens...

1RXS J180834.7+101041 is a new cataclysmic variable with non-uniform disc

Science.gov (United States)

Yakin, D. G.; Suleimanov, V. F.; Shimansky, V. V.; Borisov, N. V.; Bikmaev, I. F.; Sakhibullin, N. A.

2010-11-01

Results of photometric and spectroscopic investigations of the recently discovered disc cataclysmic variable star 1RXS J180834.7+101041 are presented. Emission spectra of the system show broad double peaked hydrogen and helium emission lines. Doppler maps for the hydrogen lines demonstrate strongly non-uniform emissivity distribution in the disc, similar to that found in IP Peg. It means that the system is a new cataclysmic variable with a spiral density wave in the disc. Masses of the components (MWD = 0.8+/-0.22 Msolar and MRD = 0.14+/-0.02 Msolar), and the orbit inclination (i = 78°+/- 1.°5) were estimated using the various well-known relations for cataclysmic variables.

Equilibrium, kinetics and thermodynamics studies of chitosan-based solid phase nanoparticles as sorbent for lead (II) cations from aqueous solution

Energy Technology Data Exchange (ETDEWEB)

Shaker, Medhat A., E-mail: drmashaker@yahoo.com [Current address: Chemistry Department, Faculty of Science, University of Jeddah, Jeddah (Saudi Arabia); Permanent address: Chemistry Department, Faculty of Science, Damanhour University, Damanhour (Egypt)

2015-07-15

Ternary nanoparticles of chitosan, non-viable biomass (Pseudomonas sp.) and gelatin, CPG were synthesized by chemical crosslinking method and applied as a novel and cost-effective solid phase to adsorb Pb(II) cations from aqueous solution. Characterization of the fabricated CPG nanoparticles and their complexation behavior were extensively interrogated by dynamic light scattering (DLS), FTIR, TGA, XRD and SEM techniques. The extent of adsorption was found to be a function of medium pH, contact time, initial Pb(II) concentration and temperature. The Langmuir, Freundlich, Dubinin–Radushkevich and Redlich–Peterson models were used to illustrate the isotherms of the adsorption system. The adsorption of Pb(II) cations onto CPG best-fits the Langmuir isotherm model which predicts two stoichiometric temperature-independent adsorption sites, A and B with variable capacities, 35.4 and 91.1 mg g{sup −1}, respectively and removal capacity above 90%. Thermodynamic studies revealed that the adsorption process was physical, spontaneous, and endothermic. The adsorption rate is influenced by temperature and the adsorption kinetic is well confirmed with pseudo-second-order equation compared with three other investigated kinetic models. Present study indicated potential applications of CPG nanoparticles as excellent natural and promising solid phase for Pb(II) extraction in wastewater treatment. - Graphical abstract: Display Omitted - Highlights: • Kinetics and thermodynamics of Pb{sup 2+} biosorption onto CPG nanoparticles are studied. • Adsorption kinetic data are best modeled using second-order rate equations. • The Pb{sup 2}adsorption onto CPG was physical diffusion controlled reaction. • The experimental equilibrium results well fit the Langmuir model. • The thermodynamics show endothermic, favorable and spontaneous adsorption processes.

Non-CpG methylation of the PGC-1alpha promoter through DNMT3B controls mitochondrial density

DEFF Research Database (Denmark)

Barres, Romain; Osler, Megan E; Yan, Jie

2009-01-01

-CpG nucleotides. Non-CpG methylation was acutely increased in human myotubes by exposure to tumor necrosis factor-alpha (TNF-alpha) or free fatty acids, but not insulin or glucose. Selective silencing of the DNA methyltransferase 3B (DNMT3B), but not DNMT1 or DNMT3A, prevented palmitate-induced non......-CpG methylation of PGC-1alpha and decreased mtDNA and PGC-1alpha mRNA. We provide evidence for PGC-1alpha hypermethylation, concomitant with reduced mitochondrial content in type 2 diabetic patients, and link DNMT3B to the acute fatty-acid-induced non-CpG methylation of PGC-1alpha promoter....

Isocitrate dehydrogenase 1 R132C mutation occurs exclusively in microsatellite stable colorectal cancers with the CpG island methylator phenotype

OpenAIRE

Whitehall, VLJ; Dumenil, TD; McKeone, DM; Bond, CE; Bettington, ML; Buttenshaw, RL; Bowdler, L; Montgomery, GW; Wockner, LF; Leggett, BA

2014-01-01

The CpG Island Methylator Phenotype (CIMP) is fundamental to an important subset of colorectal cancer; however, its cause is unknown. CIMP is associated with microsatellite instability but is also found in BRAF mutant microsatellite stable cancers that are associated with poor prognosis. The isocitrate dehydrogenase 1 (IDH1) gene causes CIMP in glioma due to an activating mutation that produces the 2-hydroxyglutarate oncometabolite. We therefore examined IDH1 alteration as a potential cause o...

DNA Methylation at a Bovine Alpha Satellite I Repeat CpG Site during Development following Fertilization and Somatic Cell Nuclear Transfer

OpenAIRE

Couldrey, Christine; Wells, David N.

2013-01-01

Incomplete epigenetic reprogramming is postulated to contribute to the low developmental success following somatic cell nuclear transfer (SCNT). Here, we describe the epigenetic reprogramming of DNA methylation at an alpha satellite I CpG site (αsatI-5) during development of cattle generated either by artificial insemination (AI) or in vitro fertilization (IVF) and SCNT. Quantitative methylation analysis identified that SCNT donor cells were highly methylated at αsatI-5 and resulting SCNT bla...

Clean Water Act (excluding Section 404)

Energy Technology Data Exchange (ETDEWEB)

1993-01-15

This Reference Book contains a current copy of the Clean Water Act (excluding Section 404) and those regulations that implement the statutes and appear to be most relevant to US Department of Energy (DOE) activities. The document is provided to DOE and contractor staff for informational purposes only and should not be interpreted as legal guidance. Updates that include important new requirements will be provided periodically. Questions concerning this Reference Book may be directed to Mark Petts, EH-231 (202/586-2609).

Extended Excluded Volume: Its Origin and Consequences

Czech Academy of Sciences Publication Activity Database

Nezbeda, Ivo; Rouha, M.

2013-01-01

Roč. 85, č. 1 (2013), s. 201-210 ISSN 0033-4545. [International Conference on Solution Chemistry (ICSC-32) /32./. La Grande Motte, 28.08.2011-02.09.2011] R&D Projects: GA AV ČR IAA400720802 Institutional support: RVO:67985858 Keywords : excluded volume * partial molar volume * primitive models Subject RIV: CF - Physical ; Theoretical Chemistry Impact factor: 3.112, year: 2013

Development of a non-piston MR suspension rod for variable mass systems

Science.gov (United States)

Deng, Huaxia; Han, Guanghui; Zhang, Jin; Wang, Mingxian; Ma, Mengchao; Zhong, Xiang; Yu, Liandong

2018-06-01

The semi-active suspension systems for variable mass systems require long work stroke and variable damping, while the currently piston structure limits the work stroke for the magnetorheological (MR) dampers. The main work of this paper is to design a semi-active non-piston MR (NPMR) suspension rod for the reduction of the vibration of an automatic impeller washing machine, which is a typical variable mass system. The designed suspension rod locates in the suspension system that links the internal tub to the washing machine cabinet. The NPMR suspension rod includes a MR part and a air part. The MR part can provide low initial damping force and the unlimited work stroke compared with the piston MR damper. The hysteretic response tests and vibration performance evaluation with different loadings are conducted to verify the dynamic performance for the designed rod. The measured damping force of the MR part varies from 5 to 20 N. Studies of dehydration mode experiments of the washing machine indicate that its vibration acceleration with the NPMR suspension rods can reduce to half of the original passive ones in certain conditions.

8 CFR 1240.38 - Fingerprinting of excluded aliens.

Science.gov (United States)

2010-01-01

... 8 Aliens and Nationality 1 2010-01-01 2010-01-01 false Fingerprinting of excluded aliens. 1240.38 Section 1240.38 Aliens and Nationality EXECUTIVE OFFICE FOR IMMIGRATION REVIEW, DEPARTMENT OF JUSTICE IMMIGRATION REGULATIONS PROCEEDINGS TO DETERMINE REMOVABILITY OF ALIENS IN THE UNITED STATES Exclusion of...

Differential production of immunoglobulin classes and subclasses by mucosal-type human B-lymphocytes exposed in vitro to CpG oligodeoxynucleotides.

Science.gov (United States)

Cognasse, Fabrice; Acquart, Sophie; Beniguel, Lydie; Sabido, Odile; Chavarin, Patricia; Genin, Christian; Garraud, Olivier

2005-01-01

As B-lymphocytes play an important role in innate and adaptive immunity, we aimed to examine the effects of CpG oligodeoxynucleotides (ODNs) on purified tonsil-originating CD19+ B-cells, representing mucosal B-cells. We screened various K-type ODNs, reactive with human B-cells, and tested for the production of immunoglobulins in vitro. Using one CpG-ODN, DSP30, we observed that it could upregulate not only Toll-like receptor 9 (TLR9) mRNA expression in activated B-cells, but also the early expression of CD69 followed by the sequential expression of CD80, CD86 and the nuclear factor (NF)-kappaB pathway. Furthermore, mRNA expression of certain B-cell-derived cytokines was influenced by exposure to DSP30, with a strong upregulation of interleukin 6 (IL-6) and downregulation of IL1-beta. Stimulation of B-cells, co-stimulated with IL-2, IL-10 and soluble CD40 ligand (sCD40L) with different CpG-ODNs, had differing effects on the terminal differentiation in vitro of B-cells into immunoglobulin-secreting cells. TLR9 is involved in innate immunity and the recognition of bound CpG DNA from invading bacterial pathogens. As tonsillar B-cells are mucosal-type B-lymphocytes, this study suggests that CpG-ODNs show promise as mucosal adjuvants in modulating the local production of immunoglobulins of certain classes and subclasses, a crucial issue in vaccine perspectives.

A non-local hidden-variable model that violates Leggett-type inequalities

Energy Technology Data Exchange (ETDEWEB)

Zela, F de [Departamento de Ciencias, Seccion Fisica, Pontificia Universidad Catolica del Peru, Apartado 1761, Lima (Peru)

2008-12-19

Recent experiments of Groeblacher et al proved the violation of a Leggett-type inequality that was claimed to be valid for a broad class of non-local hidden-variable theories. The impossibility of constructing a non-local and realistic theory, unless it entails highly counterintuitive features, seems thus to have been experimentally proved. This would bring us close to a definite refutation of realism. Indeed, realism was proved to be also incompatible with locality, according to a series of experiments testing Bell inequalities. The present paper addresses the said experiments of Groeblacher et al and presents an explicit, contextual and realistic, model that reproduces the predictions of quantum mechanics. It thus violates the Leggett-type inequality that was established with the aim of ruling out a supposedly broad class of non-local models. We can thus conclude that plausible contextual, realistic, models are still tenable. This restates the possibility of a future completion of quantum mechanics by a realistic and contextual theory which is not in a class containing only highly counterintuitive models. The class that was ruled out by the experiments of Groeblacher et al is thus proved to be a limited one, arbitrarily separating models that physically belong in the same class.

A non-local hidden-variable model that violates Leggett-type inequalities

International Nuclear Information System (INIS)

Zela, F de

2008-01-01

Recent experiments of Groeblacher et al proved the violation of a Leggett-type inequality that was claimed to be valid for a broad class of non-local hidden-variable theories. The impossibility of constructing a non-local and realistic theory, unless it entails highly counterintuitive features, seems thus to have been experimentally proved. This would bring us close to a definite refutation of realism. Indeed, realism was proved to be also incompatible with locality, according to a series of experiments testing Bell inequalities. The present paper addresses the said experiments of Groeblacher et al and presents an explicit, contextual and realistic, model that reproduces the predictions of quantum mechanics. It thus violates the Leggett-type inequality that was established with the aim of ruling out a supposedly broad class of non-local models. We can thus conclude that plausible contextual, realistic, models are still tenable. This restates the possibility of a future completion of quantum mechanics by a realistic and contextual theory which is not in a class containing only highly counterintuitive models. The class that was ruled out by the experiments of Groeblacher et al is thus proved to be a limited one, arbitrarily separating models that physically belong in the same class

Modeling Linguistic Variables With Regression Models: Addressing Non-Gaussian Distributions, Non-independent Observations, and Non-linear Predictors With Random Effects and Generalized Additive Models for Location, Scale, and Shape

Directory of Open Access Journals (Sweden)

Christophe Coupé

2018-04-01

Full Text Available As statistical approaches are getting increasingly used in linguistics, attention must be paid to the choice of methods and algorithms used. This is especially true since they require assumptions to be satisfied to provide valid results, and because scientific articles still often fall short of reporting whether such assumptions are met. Progress is being, however, made in various directions, one of them being the introduction of techniques able to model data that cannot be properly analyzed with simpler linear regression models. We report recent advances in statistical modeling in linguistics. We first describe linear mixed-effects regression models (LMM, which address grouping of observations, and generalized linear mixed-effects models (GLMM, which offer a family of distributions for the dependent variable. Generalized additive models (GAM are then introduced, which allow modeling non-linear parametric or non-parametric relationships between the dependent variable and the predictors. We then highlight the possibilities offered by generalized additive models for location, scale, and shape (GAMLSS. We explain how they make it possible to go beyond common distributions, such as Gaussian or Poisson, and offer the appropriate inferential framework to account for ‘difficult’ variables such as count data with strong overdispersion. We also demonstrate how they offer interesting perspectives on data when not only the mean of the dependent variable is modeled, but also its variance, skewness, and kurtosis. As an illustration, the case of phonemic inventory size is analyzed throughout the article. For over 1,500 languages, we consider as predictors the number of speakers, the distance from Africa, an estimation of the intensity of language contact, and linguistic relationships. We discuss the use of random effects to account for genealogical relationships, the choice of appropriate distributions to model count data, and non-linear relationships

Modeling Linguistic Variables With Regression Models: Addressing Non-Gaussian Distributions, Non-independent Observations, and Non-linear Predictors With Random Effects and Generalized Additive Models for Location, Scale, and Shape.

Science.gov (United States)

Coupé, Christophe

2018-01-01

As statistical approaches are getting increasingly used in linguistics, attention must be paid to the choice of methods and algorithms used. This is especially true since they require assumptions to be satisfied to provide valid results, and because scientific articles still often fall short of reporting whether such assumptions are met. Progress is being, however, made in various directions, one of them being the introduction of techniques able to model data that cannot be properly analyzed with simpler linear regression models. We report recent advances in statistical modeling in linguistics. We first describe linear mixed-effects regression models (LMM), which address grouping of observations, and generalized linear mixed-effects models (GLMM), which offer a family of distributions for the dependent variable. Generalized additive models (GAM) are then introduced, which allow modeling non-linear parametric or non-parametric relationships between the dependent variable and the predictors. We then highlight the possibilities offered by generalized additive models for location, scale, and shape (GAMLSS). We explain how they make it possible to go beyond common distributions, such as Gaussian or Poisson, and offer the appropriate inferential framework to account for 'difficult' variables such as count data with strong overdispersion. We also demonstrate how they offer interesting perspectives on data when not only the mean of the dependent variable is modeled, but also its variance, skewness, and kurtosis. As an illustration, the case of phonemic inventory size is analyzed throughout the article. For over 1,500 languages, we consider as predictors the number of speakers, the distance from Africa, an estimation of the intensity of language contact, and linguistic relationships. We discuss the use of random effects to account for genealogical relationships, the choice of appropriate distributions to model count data, and non-linear relationships. Relying on GAMLSS, we

21 CFR 1404.950 - Excluded Parties List System

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 9 2010-04-01 2010-04-01 false Excluded Parties List System 1404.950 Section 1404.950 Food and Drugs OFFICE OF NATIONAL DRUG CONTROL POLICY GOVERNMENTWIDE DEBARMENT AND SUSPENSION... other information about persons who are ineligible. The EPLS system includes the printed version...

The Education Act and Excluded Children. Policy Review.

Science.gov (United States)

Hodgkin, Rachel

1997-01-01

Discusses the negative assumptions and outcomes of provisions in Britain's Education Act of 1997 dealing with expulsion of students. Presents some statistics on excluded children; discusses likely outcomes such as increased delinquency, parent-school acrimony, and disparity in schools. Describes the role of teachers' unions in drafting the bill…

Comparing Facebook Users and Facebook Non-Users: Relationship between Personality Traits and Mental Health Variables – An Exploratory Study

Science.gov (United States)

2016-01-01

Over one billion people use Facebook as a platform for social interaction and self-presentation making it one of the most popular online sites. The aim of the present study was to investigate differences in various personality traits and mental health variables between Facebook users and people who do not use this platform. The data of 945 participants (790 Facebook users, 155 Facebook non-users) were collected. Results indicate that Facebook users score significantly higher on narcissism, self-esteem and extraversion than Facebook non-users. Furthermore, they have significantly higher values of social support, life satisfaction and subjective happiness. Facebook non-users have (marginally) significantly higher values of depression symptoms than Facebook users. In both groups, extraversion, self-esteem, happiness, life satisfaction, resilience and social support, on the one hand, and depression, anxiety and stress symptoms, on the other hand, are negatively correlated. Neuroticism is positively associated with depression, anxiety and stress symptoms. However, significant differences exist between Facebook users and Facebook non-users regarding some associations of personality traits and mental health variables. Compared to Facebook non-users, the present results indicate that Facebook users have higher values of certain personality traits and positive variables protecting mental health. These findings are of particular interest considering the high importance of social online-platforms in the daily life of many people. PMID:27907020

Direct estimation and correction of bias from temporally variable non-stationary noise in a channelized Hotelling model observer.

Science.gov (United States)

Fetterly, Kenneth A; Favazza, Christopher P

2016-08-07

Channelized Hotelling model observer (CHO) methods were developed to assess performance of an x-ray angiography system. The analytical methods included correction for known bias error due to finite sampling. Detectability indices ([Formula: see text]) corresponding to disk-shaped objects with diameters in the range 0.5-4 mm were calculated. Application of the CHO for variable detector target dose (DTD) in the range 6-240 nGy frame(-1) resulted in [Formula: see text] estimates which were as much as 2.9×  greater than expected of a quantum limited system. Over-estimation of [Formula: see text] was presumed to be a result of bias error due to temporally variable non-stationary noise. Statistical theory which allows for independent contributions of 'signal' from a test object (o) and temporally variable non-stationary noise (ns) was developed. The theory demonstrates that the biased [Formula: see text] is the sum of the detectability indices associated with the test object [Formula: see text] and non-stationary noise ([Formula: see text]). Given the nature of the imaging system and the experimental methods, [Formula: see text] cannot be directly determined independent of [Formula: see text]. However, methods to estimate [Formula: see text] independent of [Formula: see text] were developed. In accordance with the theory, [Formula: see text] was subtracted from experimental estimates of [Formula: see text], providing an unbiased estimate of [Formula: see text]. Estimates of [Formula: see text] exhibited trends consistent with expectations of an angiography system that is quantum limited for high DTD and compromised by detector electronic readout noise for low DTD conditions. Results suggest that these methods provide [Formula: see text] estimates which are accurate and precise for [Formula: see text]. Further, results demonstrated that the source of bias was detector electronic readout noise. In summary, this work presents theory and methods to test for the

Characterization of the antigen-specific CD4+ T cell response induced by prime-boost strategies with CAF01 and CpG adjuvants administered by the intranasal and subcutaneous routes

Directory of Open Access Journals (Sweden)

Annalisa eCiabattini

2015-08-01

Full Text Available The design of heterologous prime-boost vaccine combinations that optimally shape the immune response is of critical importance for the development of next generation vaccines. Here we tested different prime-boost combinations using the tuberculosis vaccine antigen H56 with CAF01 or CpG ODN 1821 adjuvants, administered by the parenteral and nasal routes. By using peptide-MHC class II tetramers, antigen-specific CD4+ T cells were tracked following primary and booster immunizations. Both parenteral priming with H56 plus CAF01 and nasal priming with H56 plus CpG elicited significant expansion of CD4+ tetramer-positive T cells in the spleen, however only parenterally primed cells responded to booster immunization. Subcutaneous priming with H56 and CAF01 followed by nasal boosting with H56 and CpG showed the greater expansion of CD4+ tetramer-positive T cells in the spleen and lungs compared to all the other homologous and heterologous prime-boost combinations. Nasal boosting exerted a recruitment of primed CD4+ T cells into lungs that was stronger in subcutaneously than nasally primed mice, in accordance with different chemokine receptor expression induced by primary immunization. These data demonstrate that subcutaneous priming is fundamental for eliciting CD4+ T cells that can be efficiently boosted by the nasal route and results in the recruitment of antigen-experienced cells into the lungs. Combination of different vaccine formulations and routes of delivery for priming and boosting is a strategic approach for improving and directing vaccine-induced immune responses.

Excluded-volume effects in the diffusion of hard spheres

KAUST Repository

Bruna, Maria; Chapman, S. Jonathan

2012-01-01

Excluded-volume effects can play an important role in determining transport properties in diffusion of particles. Here, the diffusion of finite-sized hard-core interacting particles in two or three dimensions is considered systematically using

Excluded-Mean-Variance Neural Decision Analyzer for Qualitative Group Decision Making

Directory of Open Access Journals (Sweden)

Ki-Young Song

2012-01-01

Full Text Available Many qualitative group decisions in professional fields such as law, engineering, economics, psychology, and medicine that appear to be crisp and certain are in reality shrouded in fuzziness as a result of uncertain environments and the nature of human cognition within which the group decisions are made. In this paper we introduce an innovative approach to group decision making in uncertain situations by using a mean-variance neural approach. The key idea of this proposed approach is to compute the excluded mean of individual evaluations and weight it by applying a variance influence function (VIF; this process of weighting the excluded mean by VIF provides an improved result in the group decision making. In this paper, a case study with the proposed excluded-mean-variance approach is also presented. The results of this case study indicate that this proposed approach can improve the effectiveness of qualitative decision making by providing the decision maker with a new cognitive tool to assist in the reasoning process.

TLR9 expression in glioma tissues correlated to glioma progression and the prognosis of GBM patients

International Nuclear Information System (INIS)

Wang, Chao; Cao, Shouqiang; Yan, Ying; Ying, Qiao; Jiang, Tao; Xu, Ke; Wu, Anhua

2010-01-01

Our study aims to evaluate the expression of TLR9 in glioma tissues, examine the association between TLR9 expression, clinicopathological variables, and glioma patient outcome, we further characterized the direct effects of TLR9 agonist CpG ODN upon the proliferation and invasion of glioma cells in vitro. RT-PCR and immunofluorescence were used to determine the expression of TLR9 in glioma cell lines and clinical glioma samples. Tissue microarry and immunohistochemistry were applied to evaluated TLR9 expression in 292 newly diagnosed glioma and 13 non-neoplastic brain tissues. We further investigated the effect of CpG ODN on the proliferation and invasion of glioma cells in vitro with MTT assays and matrigel transwell assay respectively. RT-PCR showed that TLR9 expressed in all the glioma samples and glioma cell lines we examined. The tissue array analysis indicated that TLR9 expression is correlated with malignancy of glioma (p < 0.01). Multivariate Cox regression analysis revealed that TLR9 expression is an independent prognostic factor for PFS of GBM patients(P = 0.026). TLR9 agonist CpG ODN has no significant effect on glioma proliferation, but matrigel transwell analysis showed that TLR9 agonist CpG ODN can significantly enhance glioma invasion in vitro. Our data indicated that TLR9 expression increases according to the histopathological grade of glioma, and the TLR9 expression level is related to the PFS of GBM patients. In addition, our findings warrant caution in the directly injection of TLR9 agonist CpG ODN into glioma tissues for the glioma immunotherapy

The Cambridge Prognostic Groups for improved prediction of disease mortality at diagnosis in primary non-metastatic prostate cancer: a validation study.

Science.gov (United States)

Gnanapragasam, V J; Bratt, O; Muir, K; Lee, L S; Huang, H H; Stattin, P; Lophatananon, A

2018-02-28

The purpose of this study is to validate a new five-tiered prognostic classification system to better discriminate cancer-specific mortality in men diagnosed with primary non-metastatic prostate cancer. We applied a recently described five-strata model, the Cambridge Prognostic Groups (CPGs 1-5), in two international cohorts and tested prognostic performance against the current standard three-strata classification of low-, intermediate- or high-risk disease. Diagnostic clinico-pathological data for men obtained from the Prostate Cancer data Base Sweden (PCBaSe) and the Singapore Health Study were used. The main outcome measure was prostate cancer mortality (PCM) stratified by age group and treatment modality. The PCBaSe cohort included 72,337 men, of whom 7162 died of prostate cancer. The CPG model successfully classified men with different risks of PCM with competing risk regression confirming significant intergroup distinction (p study of nearly 75,000 men confirms that the CPG five-tiered prognostic model has superior discrimination compared to the three-tiered model in predicting prostate cancer death across different age and treatment groups. Crucially, it identifies distinct sub-groups of men within the old intermediate-risk and high-risk criteria who have very different prognostic outcomes. We therefore propose adoption of the CPG model as a simple-to-use but more accurate prognostic stratification tool to help guide management for men with newly diagnosed prostate cancer.

Effects of probiotics, probiotic DNA and the CpG oligodeoxynucleotides on ovalbumin-sensitized Brown-Norway rats via TLR9/NF-κB pathway.

Science.gov (United States)

Zhong, Yan; Huang, Juan; Tang, Wenjing; Chen, Bing; Cai, Wei

2012-10-01

The aim of the study was to investigate the effect of living probiotics, probiotic DNA and the synthetic oligodeoxynucleotides containing CpG motifs (CpG-ODN) on both immune response and intestinal barrier function in ovalbumin-sensitized rat and the underlying mechanisms. Brown-Norway rats were orally sensitized with ovalbumin, and living probiotics, probiotic DNA extraction, synthetic CpG-ODN or non-CpG ODN control was administered. In the living probiotics, probiotic DNA and CpG-ODN groups, the allergic response was significantly inhibited, the Th1/Th2 cytokine balance was shifted away from Th2 side, the percentage of CD4(+) CD25(+high) Treg cells was increased, and the intestinal barrier function was improved. The levels of toll-like receptor (TLR) 9 mRNA and nuclear factor (NF)-κB activity, as well as the IκB-α phosphorylation (p-IκB-α) was significantly increased in these three intervention groups compared with the OVA-positive group, whereas no such effects were found in the non-CpG ODN control group. These data show that the probiotic genomic DNA and the synthetic CpG-ODN was comparable with living probiotics in preventing food allergic response by immune modulation and intestinal barrier function enhancement, and the activation of TLR9/NF-κB signal pathway might be involved in this process. © 2012 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.

Functional Characterization and Drug Response of Freshly Established Patient-Derived Tumor Models with CpG Island Methylator Phenotype.

Directory of Open Access Journals (Sweden)

Claudia Maletzki

Full Text Available Patient-individual tumor models constitute a powerful platform for basic and translational analyses both in vitro and in vivo. However, due to the labor-intensive and highly time-consuming process, only few well-characterized patient-derived cell lines and/or corresponding xenografts exist. In this study, we describe successful generation and functional analysis of novel tumor models from patients with sporadic primary colorectal carcinomas (CRC showing CpG island methylator phenotype (CIMP. Initial DNA fingerprint analysis confirmed identity with the patient in all four cases. These freshly established cells showed characteristic features associated with the CIMP-phenotype (HROC40: APCwt, TP53 mut, KRAS mut; 3/8 marker methylated; HROC43: APC mut, TP53 mut, KRAS mut; 4/8 marker methylated; HROC60: APCwt, TP53 mut, KRASwt; 4/8 marker methylated; HROC183: APC mut, TP53 mut, KRAS mut; 6/8 marker methylated. Cell lines were of epithelial origin (EpCAM+ with distinct morphology and growth kinetics. Response to chemotherapeutics was quite individual between cells, with stage I-derived cell line HROC60 being most susceptible towards standard clinically approved chemotherapeutics (e.g. 5-FU, Irinotecan. Of note, most cell lines were sensitive towards "non-classical" CRC standard drugs (sensitivity: Gemcitabin > Rapamycin > Nilotinib. This comprehensive analysis of tumor biology, genetic alterations and assessment of chemosensitivity towards a broad range of (chemo- therapeutics helps bringing forward the concept of personalized tumor therapy.

Capacity of non-invasive hepatic fibrosis algorithms to replace transient elastography to exclude cirrhosis in people with hepatitis C virus infection: A multi-centre observational study.

Science.gov (United States)

Kelly, Melissa Louise; Riordan, Stephen M; Bopage, Rohan; Lloyd, Andrew R; Post, Jeffrey John

2018-01-01

Achievement of the 2030 World Health Organisation (WHO) global hepatitis C virus (HCV) elimination targets will be underpinned by scale-up of testing and use of direct-acting antiviral treatments. In Australia, despite publically-funded testing and treatment, less than 15% of patients were treated in the first year of treatment access, highlighting the need for greater efficiency of health service delivery. To this end, non-invasive fibrosis algorithms were examined to reduce reliance on transient elastography (TE) which is currently utilised for the assessment of cirrhosis in most Australian clinical settings. This retrospective and prospective study, with derivation and validation cohorts, examined consecutive patients in a tertiary referral centre, a sexual health clinic, and a prison-based hepatitis program. The negative predictive value (NPV) of seven non-invasive algorithms were measured using published and newly derived cut-offs. The number of TEs avoided for each algorithm, or combination of algorithms, was determined. The 850 patients included 780 (92%) with HCV mono-infection, and 70 (8%) co-infected with HIV or hepatitis B. The mono-infected cohort included 612 men (79%), with an overall prevalence of cirrhosis of 16% (125/780). An 'APRI' algorithm cut-off of 1.0 had a 94% NPV (95%CI: 91-96%). Newly derived cut-offs of 'APRI' (0.49), 'FIB-4' (0.93) and 'GUCI' (0.5) algorithms each had NPVs of 99% (95%CI: 97-100%), allowing avoidance of TE in 40% (315/780), 40% (310/780) and 40% (298/749) respectively. When used in combination, NPV was retained and TE avoidance reached 54% (405/749), regardless of gender or co-infection. Non-invasive algorithms can reliably exclude cirrhosis in many patients, allowing improved efficiency of HCV assessment services in Australia and worldwide.

Diffusion of multiple species with excluded-volume effects

KAUST Repository

Bruna, Maria; Chapman, S. Jonathan

2012-01-01

Stochastic models of diffusion with excluded-volume effects are used to model many biological and physical systems at a discrete level. The average properties of the population may be described by a continuum model based on partial differential equations. In this paper we consider multiple interacting subpopulations/species and study how the inter-species competition emerges at the population level. Each individual is described as a finite-size hard core interacting particle undergoing Brownian motion. The link between the discrete stochastic equations of motion and the continuum model is considered systematically using the method of matched asymptotic expansions. The system for two species leads to a nonlinear cross-diffusion system for each subpopulation, which captures the enhancement of the effective diffusion rate due to excluded-volume interactions between particles of the same species, and the diminishment due to particles of the other species. This model can explain two alternative notions of the diffusion coefficient that are often confounded, namely collective diffusion and self-diffusion. Simulations of the discrete system show good agreement with the analytic results. © 2012 American Institute of Physics.

Comparative anatomy of the human APRT gene and enzyme: nucleotide sequence divergence and conservation of a nonrandom CpG dinucleotide arrangement

International Nuclear Information System (INIS)

Broderick, T.P.; Schaff, D.A.; Bertino, A.M.; Dush, M.K.; Tischfield, J.A.; Stambrook, P.J.

1987-01-01

The functional human adenine phosphoribosyltransferase (APRT) gene is <2.6 kilobases in length and contains five exons. The amino acid sequences of APRTs have been highly conserved throughout evolution. The human enzyme is 82%, 90%, and 40% identical to the mouse, hamster, and Escherichia coli enzymes, respectively. The promoter region of the human APRT gene, like that of several other housekeeping genes, lacks TATA and CCAAT boxes but contains five GC boxes that are potential binding sites for the Sp1 transcription factor. The distal three, however, are dispensable for gene expression. Comparison between human and mouse APRT gene nucleotide sequences reveals a high degree of homology within protein coding regions but an absence of significant homology in 5' flanking, 3' untranslated, and intron sequences, except for similarly positioned GC boxes in the promoter region and a 26-base-pair region in intron 3. This 26-base-pair sequence is 92% identical with a similarly positioned sequence in the mouse gene and is also found in intron 3 of the hamster gene, suggesting that its retention may be a consequence of stringent selection. The positions of all introns have been precisely retained in the human and both rodent genes. Retention of an elevated CpG dinucleotide content, despite loss of sequence homology, suggests that there may be selection for CpG dinucleotides in these regions and that their maintenance may be important for APRT gene function

Pharmaceutical Cognitive Enhancement in Greek University Students: Differences Between Users and Non-Users in Social Cognitive Variables, Burnout, and Engagement.

Science.gov (United States)

Lazuras, Lambros; Ypsilanti, Antonia; Lamprou, Efthymios; Kontogiorgis, Christos

2017-06-07

Pharmaceutical cognitive enhancement (PCE) represents the non-medical use of prescribed medication for the improvement of cognitive functioning and academic performance. Although there are some studies about PCE prevalence, it is less clear how users and non-users of PCE substances differ with respect to their positive and negative student experiences (e.g. academic burnout and engagement with studies) and in social cognitive variables that relate to decision-making and self-regulation of PCE use. The present study assessed whether students with different experiences of PCE substance use displayed differences in academic burnout, study engagement, and social cognitive variables relevant to PCE use. Three hundred and forty-seven university students (mean age (M) = 22.15 years, SD = 1.69; 54% females) completed a battery of anonymous questionnaires on academic burnout, engagement with studies, social cognitive variables relevant to PCE use, and self-reported use of PCE substances and non-prescribed nutritional supplements. Three user groups emerged, namely non-users (51.9%, n = 180), single users of non-prescribed dietary supplements (25.4%, n = 88), and dual users of both non-prescribed dietary supplements and PCE (22.8%, n = 79). Multivariate analysis of variance indicated significant differences among the three user groups in intentions, attitudes, social norms, and anticipated regret toward PCE use. No significant differences were observed with respect to academic burnout and work engagement. The findings show that university students may engage in PCE use independent of their student experiences. Rather, a chemically assisted performance enhancement mindset seems to differentiate users from non-users of PCE substances.

Pan-cancer stratification of solid human epithelial tumors and cancer cell lines reveals commonalities and tissue-specific features of the CpG island methylator phenotype.

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Sánchez-Vega, Francisco; Gotea, Valer; Margolin, Gennady; Elnitski, Laura

2015-01-01

The term CpG island methylator phenotype (CIMP) has been used to describe widespread DNA hypermethylation at CpG-rich genomic regions affecting clinically distinct subsets of cancer patients. Even though there have been numerous studies of CIMP in individual cancer types, a uniform analysis across tissues is still lacking. We analyze genome-wide patterns of CpG island hypermethylation in 5,253 solid epithelial tumors from 15 cancer types from TCGA and 23 cancer cell lines from ENCODE. We identify differentially methylated loci that define CIMP+ and CIMP- samples, and we use unsupervised clustering to provide a robust molecular stratification of tumor methylomes for 12 cancer types and all cancer cell lines. With a minimal set of 89 discriminative loci, we demonstrate accurate pan-cancer separation of the 12 CIMP+/- subpopulations, based on their average levels of methylation. Tumor samples in different CIMP subclasses show distinctive correlations with gene expression profiles and recurrence of somatic mutations, copy number variations, and epigenetic silencing. Enrichment analyses indicate shared canonical pathways and upstream regulators for CIMP-targeted regions across cancer types. Furthermore, genomic alterations showing consistent associations with CIMP+/- status include genes involved in DNA repair, chromatin remodeling genes, and several histone methyltransferases. Associations of CIMP status with specific clinical features, including overall survival in several cancer types, highlight the importance of the CIMP+/- designation for individual tumor evaluation and personalized medicine. We present a comprehensive computational study of CIMP that reveals pan-cancer commonalities and tissue-specific differences underlying concurrent hypermethylation of CpG islands across tumors. Our stratification of solid tumors and cancer cell lines based on CIMP status is data-driven and agnostic to tumor type by design, which protects against known biases that have hindered

The ability of non-computer tasks to increase biomechanical exposure variability in computer-intensive office work.

Science.gov (United States)

Barbieri, Dechristian França; Srinivasan, Divya; Mathiassen, Svend Erik; Nogueira, Helen Cristina; Oliveira, Ana Beatriz

2015-01-01

Postures and muscle activity in the upper body were recorded from 50 academics office workers during 2 hours of normal work, categorised by observation into computer work (CW) and three non-computer (NC) tasks (NC seated work, NC standing/walking work and breaks). NC tasks differed significantly in exposures from CW, with standing/walking NC tasks representing the largest contrasts for most of the exposure variables. For the majority of workers, exposure variability was larger in their present job than in CW alone, as measured by the job variance ratio (JVR), i.e. the ratio between min-min variabilities in the job and in CW. Calculations of JVRs for simulated jobs containing different proportions of CW showed that variability could, indeed, be increased by redistributing available tasks, but that substantial increases could only be achieved by introducing more vigorous tasks in the job, in casu illustrated by cleaning.

DNA Methylation at the DAT Promoter and Risk for Psychopathology: Intergenerational Transmission between School-Age Youths and Their Parents in a Community Sample

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Silvia Cimino

2018-01-01

Full Text Available BackgroundThe effect of gene polymorphisms and promoter methylation, associated with maladaptive developmental outcomes, vary depending on environmental factors (e.g., parental psychopathology. Most studies have focused on 0- to 5-year-old children, adolescents, or adults, whereas there is dearth of research on school-age youths and pre-adolescents.MethodsIn a sample of 21 families recruited at schools, we addressed parents’ psychopathological symptoms (through SCL-90-R; offspring emotional–behavioral functioning (through CBCL-6–18; dopamine transporter gene (DAT1 for epigenetic status of the 5′-untranslated region (UTR and for genotype, i.e., variable number of tandem repeats polymorphism at the 3′-UTR. Possible associations were explored between bio-genetic and psychological characteristics within the same individual and between triplets of children, mothers, and fathers.ResultsDAT methylation of CpG at positions M1, M6, and M7 in mothers was correlated with maternal (phobic anxiety, whereas in fathers’ position M6 was related to paternal depression, anxiety, hostility, psychoticism, and higher Global Severity Index (GSI. No significant correlations were found between maternal and offspring DAT methylation. Significant correlations were found between fathers’ methylation at CpG M1 and children’s methylation at CpG M6. Linear regressions showed that mothers and fathers’ GSI predicted children’s methylation at CpG sites M2, M3, and M6, whereas fathers’ GSI predicted children’s methylation at CpG sites, particularly M1, M2, and M6. Moreover, offspring methylation of DAT at CpG M2 predicted somatic complaint, internalizing and attention problems; methylation of DAT at CpG M6 predicted withdraw.ConclusionThis study may have important clinical implication for the prevention and treatment of emotional–behavioral difficulties in children, as it adds to previous knowledge about the role of genetic and environmental factors in

Estimation of pharmacokinetic parameters from non-compartmental variables using Microsoft Excel.

Science.gov (United States)

Dansirikul, Chantaratsamon; Choi, Malcolm; Duffull, Stephen B

2005-06-01

This study was conducted to develop a method, termed 'back analysis (BA)', for converting non-compartmental variables to compartment model dependent pharmacokinetic parameters for both one- and two-compartment models. A Microsoft Excel spreadsheet was implemented with the use of Solver and visual basic functions. The performance of the BA method in estimating pharmacokinetic parameter values was evaluated by comparing the parameter values obtained to a standard modelling software program, NONMEM, using simulated data. The results show that the BA method was reasonably precise and provided low bias in estimating fixed and random effect parameters for both one- and two-compartment models. The pharmacokinetic parameters estimated from the BA method were similar to those of NONMEM estimation.

Linear versus non-linear measures of temporal variability in finger tapping and their relation to performance on open- versus closed-loop motor tasks: comparing standard deviations to Lyapunov exponents.

Science.gov (United States)

Christman, Stephen D; Weaver, Ryan

2008-05-01

The nature of temporal variability during speeded finger tapping was examined using linear (standard deviation) and non-linear (Lyapunov exponent) measures. Experiment 1 found that right hand tapping was characterised by lower amounts of both linear and non-linear measures of variability than left hand tapping, and that linear and non-linear measures of variability were often negatively correlated with one another. Experiment 2 found that increased non-linear variability was associated with relatively enhanced performance on a closed-loop motor task (mirror tracing) and relatively impaired performance on an open-loop motor task (pointing in a dark room), especially for left hand performance. The potential uses and significance of measures of non-linear variability are discussed.

Predictive Value of Beat-to-Beat QT Variability Index across the Continuum of Left Ventricular Dysfunction: Competing Risks of Non-cardiac or Cardiovascular Death, and Sudden or Non-Sudden Cardiac Death

Science.gov (United States)

Tereshchenko, Larisa G.; Cygankiewicz, Iwona; McNitt, Scott; Vazquez, Rafael; Bayes-Genis, Antoni; Han, Lichy; Sur, Sanjoli; Couderc, Jean-Philippe; Berger, Ronald D.; de Luna, Antoni Bayes; Zareba, Wojciech

2012-01-01

Background The goal of this study was to determine the predictive value of beat-to-beat QT variability in heart failure (HF) patients across the continuum of left ventricular dysfunction. Methods and Results Beat-to-beat QT variability index (QTVI), heart rate variance (LogHRV), normalized QT variance (QTVN), and coherence between heart rate variability and QT variability have been measured at rest during sinus rhythm in 533 participants of the Muerte Subita en Insuficiencia Cardiaca (MUSIC) HF study (mean age 63.1±11.7; males 70.6%; LVEF >35% in 254 [48%]) and in 181 healthy participants from the Intercity Digital Electrocardiogram Alliance (IDEAL) database. During a median of 3.7 years of follow-up, 116 patients died, 52 from sudden cardiac death (SCD). In multivariate competing risk analyses, the highest QTVI quartile was associated with cardiovascular death [hazard ratio (HR) 1.67(95%CI 1.14-2.47), P=0.009] and in particular with non-sudden cardiac death [HR 2.91(1.69-5.01), P<0.001]. Elevated QTVI separated 97.5% of healthy individuals from subjects at risk for cardiovascular [HR 1.57(1.04-2.35), P=0.031], and non-sudden cardiac death in multivariate competing risk model [HR 2.58(1.13-3.78), P=0.001]. No interaction between QTVI and LVEF was found. QTVI predicted neither non-cardiac death (P=0.546) nor SCD (P=0.945). Decreased heart rate variability (HRV) rather than increased QT variability was the reason for increased QTVI in this study. Conclusions Increased QTVI due to depressed HRV predicts cardiovascular mortality and non-sudden cardiac death, but neither SCD nor excracardiac mortality in HF across the continuum of left ventricular dysfunction. Abnormally augmented QTVI separates 97.5% of healthy individuals from HF patients at risk. PMID:22730411

The non-contact ("air puff") tonometer: variability and corneal staining.

Science.gov (United States)

Myers, K J; Scott, C A

1975-01-01

We investigated the possibility of significant corneal trauma (as revealed by slit lamp observation of the fluorescein instilled eye), and massage effects following determination of intraocular pressure with the A. O. Non-Contact tonometer (NCT). Fifteen different, normal human eyes were each applanated 150 successive times with the NCT; leading to the conclusion that only minor, superficial corneal epithelial defects sometimes resulted and that, in line with other studies, the initially higher readings (about 1 mm), obtained with the NCT, were most likely due to patient apprehension, while the subsequently lower readings represented patient acceptance of the process and were not a result of true aqueous massage. As in an earlier study, we found the instrument's variability to be about plus and minus 1 or plus and minus 2 mm and probably due to the subject's own cardiac cycle.

HumanMethylation450K Array–Identified Biomarkers Predict Tumour Recurrence/Progression at Initial Diagnosis of High-risk Non-muscle Invasive Bladder Cancer

Directory of Open Access Journals (Sweden)

Mark O Kitchen

2018-01-01

Full Text Available Background: High-risk non-muscle invasive bladder cancer (HR-NMIBC is a clinically unpredictable disease. Despite clinical risk estimation tools, many patients are undertreated with intra-vesical therapies alone, whereas others may be over-treated with early radical surgery. Molecular biomarkers, particularly DNA methylation, have been reported as predictive of tumour/patient outcomes in numerous solid organ and haematologic malignancies; however, there are few reports in HR-NMIBC and none using genome-wide array assessment. We therefore sought to identify novel DNA methylation markers of HR-NMIBC clinical outcomes that might predict tumour behaviour at initial diagnosis and help guide patient management. Patients and methods: A total of 21 primary initial diagnosis HR-NMIBC tumours were analysed by Illumina HumanMethylation450 BeadChip arrays and subsequently bisulphite Pyrosequencing. In all, 7 had not recurred at 1 year after resection and 14 had recurred and/or progressed despite intra-vesical BCG. A further independent cohort of 32 HR-NMIBC tumours (17 no recurrence and 15 recurrence and/or progression despite BCG were also assessed by bisulphite Pyrosequencing. Results: Array analyses identified 206 CpG loci that segregated non-recurrent HR-NMIBC tumours from clinically more aggressive recurrence/progression tumours. Hypermethylation of CpG cg11850659 and hypomethylation of CpG cg01149192 in combination predicted HR-NMIBC recurrence and/or progression within 1 year of diagnosis with 83% sensitivity, 79% specificity, and 83% positive and 79% negative predictive values. Conclusions: This is the first genome-wide DNA methylation analysis of a unique HR-NMIBC tumour cohort encompassing known 1-year clinical outcomes. Our analyses identified potential novel epigenetic markers that could help guide individual patient management in this clinically unpredictable disease.

CpG island methylator phenotype (CIMP) of colorectal cancer is best characterised by quantitative DNA methylation analysis and prospective cohort studies.

Science.gov (United States)

Ogino, S; Cantor, M; Kawasaki, T; Brahmandam, M; Kirkner, G J; Weisenberger, D J; Campan, M; Laird, P W; Loda, M; Fuchs, C S

2006-07-01

The concept of CpG island methylator phenotype (CIMP) is not universally accepted. Even if specific clinicopathological features have been associated with CIMP, investigators often failed to demonstrate a bimodal distribution of the number of methylated markers, which would suggest CIMP as a distinct subtype of colorectal cancer. Previous studies primarily used methylation specific polymerase chain reaction which might detect biologically insignificant low levels of methylation. To demonstrate a distinct genetic profile of CIMP colorectal cancer using quantitative DNA methylation analysis that can distinguish high from low levels of DNA methylation. We developed quantitative real time polymerase chain reaction (MethyLight) assays and measured DNA methylation (percentage of methylated reference) of five carefully selected loci (promoters of CACNA1G, CDKN2A (p16), CRABP1, MLH1, and NEUROG1) in 460 colorectal cancers from large prospective cohorts. There was a clear bimodal distribution of 80 microsatellite instability-high (MSI-H) tumours according to the number of methylated promoters, with no tumours showing 3/5 methylated loci. Thus we defined CIMP as having >or=4/5 methylated loci, and 17% (78) of the 460 tumours were classified as CIMP. CIMP was significantly associated with female sex, MSI, BRAF mutations, and wild-type KRAS. Both CIMP MSI-H tumours and CIMP microsatellite stable (MSS) tumours showed much higher frequencies of BRAF mutations (63% and 54%) than non-CIMP counterparts (non-CIMP MSI-H (0%, pCIMP MSS tumours (6.6%, pCIMP is best characterised by quantitative DNA methylation analysis. CIMP is a distinct epigenotype of colorectal cancer and may be less frequent than previously reported.

Changes in heart rate variability and QT variability during the first trimester of pregnancy.

Science.gov (United States)

Carpenter, R E; D'Silva, L A; Emery, S J; Uzun, O; Rassi, D; Lewis, M J

2015-03-01

The risk of new-onset arrhythmia during pregnancy is high, presumably relating to changes in both haemodynamic and cardiac autonomic function. The ability to non-invasively assess an individual's risk of developing arrhythmia during pregnancy would therefore be clinically significant. We aimed to quantify electrocardiographic temporal characteristics during the first trimester of pregnancy and to compare these with non-pregnant controls. Ninety-nine pregnant women and sixty-three non-pregnant women underwent non-invasive cardiovascular and haemodynamic assessment during a protocol consisting of various physiological states (postural manoeurvres, light exercise and metronomic breathing). Variables measured included stroke volume, cardiac output, heart rate, heart rate variability, QT and QT variability and QTVI (a measure of the variability of QT relative to that of RR). Heart rate (p pregnancy only during the supine position (p pregnancy in all physiological states (p pregnancy in all states (p pregnancy is associated with substantial changes in heart rate variability, reflecting a reduction in parasympathetic tone and an increase in sympathetic activity. QTVI shifted to a less favourable value, reflecting a greater than normal amount of QT variability. QTVI appears to be a useful method for quantifying changes in QT variability relative to RR (or heart rate) variability, being sensitive not only to physiological state but also to gestational age. We support the use of non-invasive markers of cardiac electrical variability to evaluate the risk of arrhythmic events in pregnancy, and we recommend the use of multiple physiological states during the assessment protocol.

University Benefits Survey. Part 1 (All Benefits Excluding Pensions).

Science.gov (United States)

University of Western Ontario, London.

Results of a 1983 survey of benefits, excluding pensions, for 17 Ontario, Canada, universities are presented. Information is provided on the following areas: whether the university self-administers insurance plans, communication of benefits, proposed changes in benefits, provision of life and dismemberment insurance, maternity leave policy,…

Transcultural Endocrinology: Adapting Type-2 Diabetes Guidelines on a Global Scale.

Science.gov (United States)

Nieto-Martínez, Ramfis; González-Rivas, Juan P; Florez, Hermes; Mechanick, Jeffrey I

2016-12-01

Type-2 diabetes (T2D) needs to be prevented and treated effectively to reduce its burden and consequences. White papers, such as evidence-based clinical practice guidelines (CPG) and their more portable versions, clinical practice algorithms and clinical checklists, may improve clinical decision-making and diabetes outcomes. However, CPG are underused and poorly validated. Protocols that translate and implement these CPG are needed. This review presents the global dimension of T2D, details the importance of white papers in the transculturalization process, compares relevant international CPG, analyzes cultural variables, and summarizes translation strategies that can improve care. Specific protocols and algorithmic tools are provided. Copyright © 2016 Elsevier Inc. All rights reserved.

LLNA variability: An essential ingredient for a comprehensive assessment of non-animal skin sensitization test methods and strategies.

Science.gov (United States)

Hoffmann, Sebastian

2015-01-01

The development of non-animal skin sensitization test methods and strategies is quickly progressing. Either individually or in combination, the predictive capacity is usually described in comparison to local lymph node assay (LLNA) results. In this process the important lesson from other endpoints, such as skin or eye irritation, to account for variability reference test results - here the LLNA - has not yet been fully acknowledged. In order to provide assessors as well as method and strategy developers with appropriate estimates, we investigated the variability of EC3 values from repeated substance testing using the publicly available NICEATM (NTP Interagency Center for the Evaluation of Alternative Toxicological Methods) LLNA database. Repeat experiments for more than 60 substances were analyzed - once taking the vehicle into account and once combining data over all vehicles. In general, variability was higher when different vehicles were used. In terms of skin sensitization potential, i.e., discriminating sensitizer from non-sensitizers, the false positive rate ranged from 14-20%, while the false negative rate was 4-5%. In terms of skin sensitization potency, the rate to assign a substance to the next higher or next lower potency class was approx.10-15%. In addition, general estimates for EC3 variability are provided that can be used for modelling purposes. With our analysis we stress the importance of considering the LLNA variability in the assessment of skin sensitization test methods and strategies and provide estimates thereof.

Office of Inspector General List of Excluded Individuals and Entities

Data.gov (United States)

U.S. Department of Health & Human Services — The objective is to ensure that providers who bill Federal health care programs do not submit claims for services furnished, ordered or prescribed by an excluded...

An entropy-variables-based formulation of residual distribution schemes for non-equilibrium flows

Science.gov (United States)

Garicano-Mena, Jesús; Lani, Andrea; Degrez, Gérard

2018-06-01

In this paper we present an extension of Residual Distribution techniques for the simulation of compressible flows in non-equilibrium conditions. The latter are modeled by means of a state-of-the-art multi-species and two-temperature model. An entropy-based variable transformation that symmetrizes the projected advective Jacobian for such a thermophysical model is introduced. Moreover, the transformed advection Jacobian matrix presents a block diagonal structure, with mass-species and electronic-vibrational energy being completely decoupled from the momentum and total energy sub-system. The advantageous structure of the transformed advective Jacobian can be exploited by contour-integration-based Residual Distribution techniques: established schemes that operate on dense matrices can be substituted by the same scheme operating on the momentum-energy subsystem matrix and repeated application of scalar scheme to the mass-species and electronic-vibrational energy terms. Finally, the performance gain of the symmetrizing-variables formulation is quantified on a selection of representative testcases, ranging from subsonic to hypersonic, in inviscid or viscous conditions.

Metastatic Ewing's sarcoma to the skull: CNS involvement excluded by MRI

Energy Technology Data Exchange (ETDEWEB)

Taets ven Amerongen, A.H.M.; Kaiser, M.C.; Waal, F.C. de

1987-03-01

A case of metastatic Ewing's sarcoma to the skull is presented, demonstrating the superiority of magnetic resonance imaging over other imaging modalities to exclude CNS involvement. Precise delineation of different tumor components in extradural location contained in an intact dural rim together with compressed cortex showing no signs of tumorous involvement constituted an MRI appearance allowing us to exclude tumor outgrowth into the brain.

Non-diffractive optically variable security devices

NARCIS (Netherlands)

Renesse, R.L. van

1991-01-01

At the past optical security conferences attention was focused on diffractive structures, e.g. holograms, embossed gratings and thin—film devices, as security elements on valuable documents. The main reasons for this emphasis are, that the iridescent effect of such diffractive optically variable

Stable phase-shift despite quasi-rhythmic movements: a CPG-driven dynamic model of active tactile exploration in an insect

Directory of Open Access Journals (Sweden)

Nalin eHarischandra

2015-08-01

Full Text Available An essential component of autonomous and flexible behaviour in animals is active exploration of the environment, allowing for perception-guided planning and control of actions. An important sensory system involved is active touch. Here, we introduce a general modelling framework of Central Pattern Generators (CPGs for movement generation in active tactile exploration behaviour. The CPG consists of two network levels: (i phase-coupled Hopf oscillators for rhythm generation, and (ii pattern formation networks for capturing the frequency and phase characteristics of individual joint oscillations. The model captured the natural, quasi-rhythmic joint kinematics as observed in coordinated antennal movements of walking stick insects. Moreover, it successfully produced tactile exploration behaviour on a three-dimensional skeletal model of the insect antennal system with physically realistic parameters. The effect of proprioceptor ablations could be simulated by changing the amplitude and offset parameters of the joint oscillators, only. As in the animal, the movement of both antennal joints was coupled with a stable phase difference, despite the quasi-rhythmicity of the joint angle time courses. We found that the phase-lead of the distal scape-pedicel joint relative to the proximal head-scape joint was essential for producing the natural tactile exploration behaviour and, thus, for tactile efficiency. For realistic movement patterns, the phase-lead could vary within a limited range of 10 to 30 degrees only. Tests with artificial movement patterns strongly suggest that this phase sensitivity is not a matter of the frequency composition of the natural movement pattern. Based on our modelling results, we propose that a constant phase difference is coded into the CPG of the antennal motor system and that proprioceptors are acting locally to regulate the joint movement amplitude.

Usefulness of Non-coplanar Helical Tomotherapy Using Variable Axis Baseplate

International Nuclear Information System (INIS)

Ha, Jin Sook; Chung, Yoon Sun; Lee, Ik Jae; Shin, Dong Bong; Kim, Jong Dae; Kim, Sei Joon; Jeon, Mi Jin; Chok, Yoon Jin; Kim, Ki Kwang; Lee, Seul Bee

2011-01-01

Helical Tomotherapy allows only coplanar beam delivery because it does not allow couch rotation. We investigated a method to introduce non-coplanar beam by tilting a patient's head for Tomotherapy. The aim of this study was to compare intrafractional movement during Tomotherapy between coplanar and non-coplanar patient's setup. Helical Tomotherapy was used for treating eight patients with intracranial tumor. The subjects were divided into three groups: one group (coplanar) of 2 patients who lay on S-plate with supine position and wore thermoplastic mask for immobilizing the head, second group (non-coplanar) of 3 patients who lay on S-plate with supine position and whose head was tilted with Variable Axis Baseplate and wore thermoplastic mask, and third group (non-coplanar plus mouthpiece) of 3 patients whose head was tilted and wore a mouthpiece immobilization device and thermoplastic mask. The patients were treated with Tomotherapy after treatment planning with Tomotherapy Planning System. Megavoltage computed tomography (MVCT) was performed before and after treatment, and the intrafractional error was measured with lateral(X), longitudinal(Y), vertical(Z) direction movements and vector (√x 2 +√y 2 +√z 2 ) value for assessing overall movement. Intrafractional error was compared among three groups by taking the error of MVCT taken after the treatment. As the correction values (X, Y, Z) between MVCT image taken after treatment and CT-simulation image are close to zero, the patient movement is small. When the mean values of movement of each direction for non-coplanar setup were compared with coplanar setup group, X-axis movement was decreased by 13%, but Y-axis and Z-axis movement were increased by 109% and 88%, respectively. Movements of Y-axis and Z-axis with non-coplanar setup were relatively greater than that of X-axis since a tilted head tended to slip down. The mean of X-axis movement of the group who used a mouthpiece was greater by 9.4% than the group

[Quality and compliance with Clinical Practice Guidelines of Chronic Noncommunicable Diseases in primary care].

Science.gov (United States)

Poblano-Verástegui, Ofelia; Vieyra-Romero, Waldo I; Galván-García, Ángel F; Fernández-Elorriaga, María; Rodríguez-Martínez, Antonia I; Saturno-Hernández, Pedro J

2017-01-01

To assess the quality and compliance of clinical practice guidelines (CPG) applicable to chronic non-communicable diseases (CNCD) in primary healthcare (CS), and views of staff on the barriers, facilitators and their use. 18 valued CPG with AGREEII, 3 are selected to develop indicators and assess compliance using lot quality acceptance sample (LQAS, standard 75 / 95% threshold 40 / 75% respectively, α:0. 05, β:0. 10) on 5 CS. 70 professionals surveyed about knowledge and use of CPG. Average quality of the CPG was 57.2%; low rating in domains: "Applicability" (<25%), "Stakeholder involvement" (43.5%) and "Rigour of development" (55.0%). Compliance in CS ranges from 39 to 53.4%. Professionals show uneven knowledge of CPG; 44 to 45% (according to CPG), they declare that they are not used, they identify as main barriers the lack of training, and their difficult accessibility and management. The quality and implementation of evaluated CPG is deficient constituting an opportunity of improvement in health services.

Radionuclide imaging of non osseous infection

International Nuclear Information System (INIS)

Palestro, C.J.; New York, Yeshiva Univ., NY; Torres, M.A.

1999-01-01

Nuclear medicine is an important tool in the diagnostic evaluation of patients with a variety of non osseous infections. In the immunocompetent population labeled leukocyte imaging is the radionuclide procedure of choice, with Gallium imaging reserved for those situations in which the leukocyte study is non diagnostic or cannot be performed. Fever of unknown origin is caused by infection in less than one-third of cases, and therefore the number of positive leukocyte studies will be relatively low. The negative leukocyte study is also useful as it has been demonstrated that a negative study excludes, with a high degree of certainty, focal infection as the cause of an FUO. In the cardiovascular system, labeled leukocyte scintigraphy is very useful for diagnosing mycotic aneurysms and infected prosthetic vascular grafts. The specificity of the study is somewhat more variable. In the central nervous system, labeled leukocyte imaging can provide important information about the etiology of contrast enhancing brain lesions identified on computed tomography. In the immunocompromised population, typified by the AIDS patient, Gallium scintigraphy is the radionuclide procedure of choice for diagnosing opportunistic diseases. In the thorax, a normal Gallium scan, in the setting of a negative chest X-ray, virtually excludes pulmonary disease. In the abdomen, Gallium is also useful for detecting nodal disease, but is not reliable for detecting large bowel disease. Labeled leukocyte imaging should be performed when colitis is a concern. Both 18 FDG PET and 201 T1 SPECT imaging of the brain are useful for distinguishing between central nervous system lymphoma and toxoplasmosis in the HIV (+) patient. On both studies, lymphoma manifests as a focus of increased tracer uptake, whereas toxoplasmosis shows little or no uptake of either tracer

Radionuclide imaging of non osseous infection

Energy Technology Data Exchange (ETDEWEB)

Palestro, C.J. (Long Island Jewish Medical Center, New York, NY, (United States). Dept. Nuclear Medicine New York, Yeshiva Univ., NY (United States). Albert Einstein College of Medicine); Torres, M.A. (Long Island Jewish Medical Center, New York, NY, (United States). Dept. Nuclear Medicine)

1999-03-01

Nuclear medicine is an important tool in the diagnostic evaluation of patients with a variety of non osseous infections. In the immunocompetent population labeled leukocyte imaging is the radionuclide procedure of choice, with Gallium imaging reserved for those situations in which the leukocyte study is non diagnostic or cannot be performed. Fever of unknown origin is caused by infection in less than one-third of cases, and therefore the number of positive leukocyte studies will be relatively low. The negative leukocyte study is also useful as it has been demonstrated that a negative study excludes, with a high degree of certainty, focal infection as the cause of an FUO. In the cardiovascular system, labeled leukocyte scintigraphy is very useful for diagnosing mycotic aneurysms and infected prosthetic vascular grafts. The specificity of the study is somewhat more variable. In the central nervous system, labeled leukocyte imaging can provide important information about the etiology of contrast enhancing brain lesions identified on computed tomography. In the immunocompromised population, typified by the AIDS patient, Gallium scintigraphy is the radionuclide procedure of choice for diagnosing opportunistic diseases. In the thorax, a normal Gallium scan, in the setting of a negative chest X-ray, virtually excludes pulmonary disease. In the abdomen, Gallium is also useful for detecting nodal disease, but is not reliable for detecting large bowel disease. Labeled leukocyte imaging should be performed when colitis is a concern. Both [sup 18]FDG PET and [sup 201]T1 SPECT imaging of the brain are useful for distinguishing between central nervous system lymphoma and toxoplasmosis in the HIV (+) patient. On both studies, lymphoma manifests as a focus of increased tracer uptake, whereas toxoplasmosis shows little or no uptake of either tracer.

Phase 1 study in malaria naïve adults of BSAM2/Alhydrogel®+CPG 7909, a blood stage vaccine against P. falciparum malaria.

Directory of Open Access Journals (Sweden)

Ruth D Ellis

Full Text Available A Phase 1 dose escalating study was conducted in malaria naïve adults to assess the safety, reactogenicity, and immunogenicity of the blood stage malaria vaccine BSAM2/Alhydrogel®+ CPG 7909. BSAM2 is a combination of the FVO and 3D7 alleles of recombinant AMA1 and MSP1(42, with equal amounts by weight of each of the four proteins mixed, bound to Alhydrogel®, and administered with the adjuvant CPG 7909. Thirty (30 volunteers were enrolled in two dose groups, with 15 volunteers receiving up to three doses of 40 µg total protein at Days 0, 56, and 180, and 15 volunteers receiving up to three doses of 160 µg protein on the same schedule. Most related adverse events were mild or moderate, but 4 volunteers experienced severe systemic reactions and two were withdrawn from vaccinations due to adverse events. Geometric mean antibody levels after two vaccinations with the high dose formulation were 136 µg/ml for AMA1 and 78 µg/ml for MSP1(42. Antibody responses were not significantly different in the high dose versus low dose groups and did not further increase after third vaccination. In vitro growth inhibition was demonstrated and was closely correlated with anti-AMA1 antibody responses. A Phase 1b trial in malaria-exposed adults is being conducted.Clinicaltrials.gov NCT00889616.

Variability of non-Gaussian diffusion MRI and intravoxel incoherent motion (IVIM) measurements in the breast.

Science.gov (United States)

Iima, Mami; Kataoka, Masako; Kanao, Shotaro; Kawai, Makiko; Onishi, Natsuko; Koyasu, Sho; Murata, Katsutoshi; Ohashi, Akane; Sakaguchi, Rena; Togashi, Kaori

2018-01-01

We prospectively examined the variability of non-Gaussian diffusion magnetic resonance imaging (MRI) and intravoxel incoherent motion (IVIM) measurements with different numbers of b-values and excitations in normal breast tissue and breast lesions. Thirteen volunteers and fourteen patients with breast lesions (seven malignant, eight benign; one patient had bilateral lesions) were recruited in this prospective study (approved by the Internal Review Board). Diffusion-weighted MRI was performed with 16 b-values (0-2500 s/mm2 with one number of excitations [NEX]) and five b-values (0-2500 s/mm2, 3 NEX), using a 3T breast MRI. Intravoxel incoherent motion (flowing blood volume fraction [fIVIM] and pseudodiffusion coefficient [D*]) and non-Gaussian diffusion (theoretical apparent diffusion coefficient [ADC] at b value of 0 sec/mm2 [ADC0] and kurtosis [K]) parameters were estimated from IVIM and Kurtosis models using 16 b-values, and synthetic apparent diffusion coefficient (sADC) values were obtained from two key b-values. The variabilities between and within subjects and between different diffusion acquisition methods were estimated. There were no statistical differences in ADC0, K, or sADC values between the different b-values or NEX. A good agreement of diffusion parameters was observed between 16 b-values (one NEX), five b-values (one NEX), and five b-values (three NEX) in normal breast tissue or breast lesions. Insufficient agreement was observed for IVIM parameters. There were no statistical differences in the non-Gaussian diffusion MRI estimated values obtained from a different number of b-values or excitations in normal breast tissue or breast lesions. These data suggest that a limited MRI protocol using a few b-values might be relevant in a clinical setting for the estimation of non-Gaussian diffusion MRI parameters in normal breast tissue and breast lesions.

An assessment of the impact of demographic, cognitive, and non-cognitive variables on student success in a community college science course

Science.gov (United States)

Mackey, Audrey Leroy

The impact of demographic, cognitive, and non-cognitive variables on academic success among community college science students was studied. Demographic variables included gender, employment status, and ethnicity. Cognitive variables included college grade point average, assessment status, course prerequisites, college course success ratios, final course grade, withdrawal patterns, and curriculum format. Non-cognitive variables included enrollment status, educational objectives, academic expectations, and career goals. The sample population included students enrolled in human anatomy courses (N = 191) at a large metropolitan community college located in central Texas. Variables that potentially influence attrition and achievement in college level science courses were examined. Final course grade and withdrawal phenomena were treated as dependent variables, while all other variables were treated as independent variables. No significant differences were found to exist between any of the demographic variables studied and the numbers of students who withdrew passing or failing. A difference was shown to be associated with the ethnicity variable and achievement levels. Educational objectives and career goals were shown to have an impact on the number of students who withdrew failing. The career goals variable and the academic expectations variable were shown to have an impact on achievement among daytime and evening students. College grade point average and course success ratios were shown to make a difference among students who withdrew passing. None of the other cognitive variables studied were shown to influence the numbers of students who withdrew passing or failing. College grade point average and course prerequisites, however, were shown to make a difference in achievement. The collaborative learning instructional format was found to have no impact on attrition or achievement, however, mean scores earned by students experiencing the collaborative learning format

Cytosine methylation at CpCpG sites triggers accumulation of non-CpG methylation in gene bodies

OpenAIRE

Zabet, NR; Catoni, Marco; Prischi, F; Paszkowski, Jerzy Waclaw

2017-01-01

Methylation of cytosine is an epigenetic mark involved in the regulation of transcription, usually associated with transcriptional repression. In mammals, methylated cytosines are found predominantly in CpGs but in plants non-CpG methylation (in the CpHpG or CpHpH contexts, where H is A, C or T) is also present and is associated with the transcriptional silencing of transposable elements. In addition, CpG methylation is found in coding regions of active genes. In the absence of the demethylas...

The Effects of Ballistic and Non-Ballistic Bench Press on Mechanical Variables.

Science.gov (United States)

Moir, Gavin L; Munford, Shawn N; Moroski, Lindsey L; Davis, Shala E

2017-02-21

To investigate the effects of ballistic and non-ballistic bench press performed with loads equivalent to 30 and 90% 1-repetition maximum (1-RM) on mechanical variables. Eleven resistance-trained men (age: 23.0 ± 1.4 years; mass: 98.4 ± 14.4 kg) attended four testing sessions where they performed one of the following sessions: 1) three sets of five non-ballistic repetitions performed with a load equivalent to 30% 1-RM (30N-B), 2) three sets of five ballistic repetitions performed with a load equivalent to 30% 1-RM (30B), 3) three sets of four non-ballistic repetitions with a load equivalent to 90% 1-RM (90N-B), 4) three sets of four ballistic repetitions with a load equivalent to 90% 1-RM (90B). Force plates and a 3-D motion analysis system were used to determine the velocity, force, power output (PO) and work during each repetition. The heavier loads resulted in significantly greater forces applied to the barbell (mean differences: 472-783 N, pvelocities (mean differences: 0.85-1.20 m/s, pvelocity (mean difference: 0.33 m/s, pbench press may be an effective exercise for developing power output and multiple sets may elicit post-activation potentiation that enhances force production. However, these benefits may be negated at heavier loads.

Non-manufacturing applications of robotics; Applications non-manufacturieres de la robotique

Energy Technology Data Exchange (ETDEWEB)

Dauchez, P. [LIRMM, Laboratoire d' Informatique, de Robotique et de Microelectronique de Montpellier, 34 (France)

2000-12-01

This book presents the different non-manufacturing sectors of activity where robotics can have useful or necessary applications: underwater robotics, agriculture robotics, road work robotics, nuclear robotics, medical-surgery robotics, aids to disabled people, entertainment robotics. Service robotics has been voluntarily excluded because this developing sector is not mature yet. (J.S.)

New operator-ordering identities and associative integration formulas of two-variable Hermite polynomials for constructing non-Gaussian states

International Nuclear Information System (INIS)

Fan Hong-Yi; Wang Zhen

2014-01-01

For directly normalizing the photon non-Gaussian states (e.g., photon added and subtracted squeezed states), we use the method of integration within an ordered product (IWOP) of operators to derive some new bosonic operator-ordering identities. We also derive some new integration transformation formulas about one- and two-variable Hermite polynomials in complex function space. These operator identities and associative integration formulas provide much convenience for constructing non-Gaussian states in quantum engineering. (general)

Comparison of 2 intravenous insulin protocols: Glycemia variability in critically ill patients.

Science.gov (United States)

Gómez-Garrido, Marta; Rodilla-Fiz, Ana M; Girón-Lacasa, María; Rodríguez-Rubio, Laura; Martínez-Blázquez, Anselmo; Martínez-López, Fernando; Pardo-Ibáñez, María Dolores; Núñez-Marín, Juan M

2017-05-01

Glycemic variability is an independent predictor of mortality in critically ill patients. The objective of this study was to compare two intravenous insulin protocols in critically ill patients regarding the glycemic variability. This was a retrospective observational study performed by reviewing clinical records of patients from a Critical Care Unit for 4 consecutive months. First, a simpler Scale-Based Intravenous Insulin Protocol (SBIIP) was reviewed and later it was compared for the same months of the following year with a Sliding Scale-Based Intravenous Insulin Protocol (SSBIIP). All adult patients admitted to the unit during the referred months were included. Patients in whom the protocol was not adequately followed were excluded. A total of 557 patients were reviewed, of whom they had needed intravenous insulin 73 in the first group and 52 in the second group. Four and two patients were excluded in each group respectively. Glycemic variability for both day 1 (DS1) and total stay (DST) was lower in SSBIIP patients compared to SBIIP patients: SD1 34.88 vs 18.16 and SDT 36.45 vs 23.65 (P<.001). A glycemic management protocol in critically ill patients based on sliding scales decreases glycemic variability. Copyright © 2017 SEEN. Publicado por Elsevier España, S.L.U. All rights reserved.

7 CFR 1794.21 - Categorically excluded proposals without an ER.

Science.gov (United States)

2010-01-01

... UTILITIES SERVICE, DEPARTMENT OF AGRICULTURE (CONTINUED) ENVIRONMENTAL POLICIES AND PROCEDURES... or the substitution of one fuel combustion technology with another is excluded from this... providing service to customers or facilities such as stock tanks and irrigation pumps. (26) New bulk...

A CpG island methylator phenotype in acute myeloid leukemia independent of IDH mutations and associated with a favorable outcome.

Science.gov (United States)

Kelly, A D; Kroeger, H; Yamazaki, J; Taby, R; Neumann, F; Yu, S; Lee, J T; Patel, B; Li, Y; He, R; Liang, S; Lu, Y; Cesaroni, M; Pierce, S A; Kornblau, S M; Bueso-Ramos, C E; Ravandi, F; Kantarjian, H M; Jelinek, J; Issa, J-Pj

2017-10-01

Genetic changes are infrequent in acute myeloid leukemia (AML) compared with other malignancies and often involve epigenetic regulators, suggesting that an altered epigenome may underlie AML biology and outcomes. In 96 AML cases including 65 pilot samples selected for cured/not-cured, we found higher CpG island (CGI) promoter methylation in cured patients. Expanded genome-wide digital restriction enzyme analysis of methylation data revealed a CGI methylator phenotype independent of IDH1/2 mutations we term AML-CGI methylator phenotype (CIMP) (A-CIMP + ). A-CIMP was associated with longer overall survival (OS) in this data set (median OS, years: A-CIMP + =not reached, CIMP - =1.17; P=0.08). For validation we used 194 samples from The Cancer Genome Atlas interrogated with Illumina 450k methylation arrays where we confirmed longer OS in A-CIMP (median OS, years: A-CIMP + =2.34, A-CIMP - =1.00; P=0.01). Hypermethylation in A-CIMP + favored CGIs (OR: CGI/non-CGI=5.21), and while A-CIMP + was enriched in CEBPA (P=0.002) and WT1 mutations (P=0.02), 70% of cases lacked either mutation. Hypermethylated genes in A-CIMP + function in pluripotency maintenance, and a gene expression signature of A-CIMP was associated with outcomes in multiple data sets. We conclude that CIMP in AML cannot be explained solely by gene mutations (for example, IDH1/2, TET2), and that curability in A-CIMP + AML should be validated prospectively.

40 CFR 761.187 - Reporting importers and by persons generating PCBs in excluded manufacturing processes.

Science.gov (United States)

2010-07-01

...) MANUFACTURING, PROCESSING, DISTRIBUTION IN COMMERCE, AND USE PROHIBITIONS General Records and Reports § 761.187 Reporting importers and by persons generating PCBs in excluded manufacturing processes. In addition to... generating PCBs in excluded manufacturing processes. 761.187 Section 761.187 Protection of Environment...

How excluding some benefits from value assessment of new drugs impacts innovation.

Science.gov (United States)

Cook, Joseph P; Golec, Joseph

2017-12-01

Payers often assess the benefits of new drugs relative to costs for reimbursement purposes, but they frequently exclude some drugs' option-related benefits, reducing their reimbursement chances, and making them less attractive R&D investments. We develop and test a real options model of R&D investment that shows that excluding option-related benefits heightens drug developers' incentives to avoid high-risk (volatile) R&D investments and instead encourages them to focus on "safer" (positively skewed) investments. Our model and empirical results could partly explain the decline in the number of risky new molecular entities. Copyright © 2017 John Wiley & Sons, Ltd.

VARIABILITY FROM NON-AXISYMMETRIC FLUCTUATIONS INTERACTING WITH STANDING SHOCKS IN TILTED BLACK HOLE ACCRETION DISKS

Energy Technology Data Exchange (ETDEWEB)

Henisey, Ken B. [Natural Science Division, Pepperdine University, Malibu, CA 90263 (United States); Blaes, Omer M. [Department of Physics, University of California, Santa Barbara, CA 93106 (United States); Fragile, P. Chris [Department of Physics and Astronomy, College of Charleston, Charleston, SC 29424 (United States)

2012-12-10

We study the spatial and temporal behavior of fluid in fully three-dimensional, general relativistic, magnetohydrodynamical simulations of both tilted and untilted black hole accretion flows. We uncover characteristically greater variability in tilted simulations at frequencies similar to those predicted by the formalism of trapped modes, but ultimately conclude that its spatial structure is inconsistent with a modal interpretation. We find instead that previously identified, transient, overdense clumps orbiting on roughly Keplerian trajectories appear generically in our global simulations, independent of tilt. Associated with these fluctuations are acoustic spiral waves interior to the orbits of the clumps. We show that the two non-axisymmetric standing shock structures that exist in the inner regions of these tilted flows effectively amplify the variability caused by these spiral waves to markedly higher levels than in untilted flows, which lack standing shocks. Our identification of clumps, spirals, and spiral-shock interactions in these fully general relativistic, magnetohydrodynamical simulations suggests that these features may be important dynamical elements in models that incorporate tilt as a way to explain the observed variability in black hole accretion flows.

Development of TRAIL Resistance by Radiation-Induced Hypermethylation of DR4 CpG Island in Recurrent Laryngeal Squamous Cell Carcinoma

International Nuclear Information System (INIS)

Lee, Jong Cheol; Lee, Won Hyeok; Min, Young Joo; Cha, Hee Jeong; Han, Myung Woul; Chang, Hyo Won; Kim, Sun-A; Choi, Seung-Ho; Kim, Seong Who; Kim, Sang Yoon

2014-01-01

Purpose: There are limited therapeutic options for patients with recurrent head and neck cancer after radiation therapy failure. To assess the use of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) as a salvage chemotherapeutic agent for recurrent cancer after radiation failure, we investigated the effect of clinically relevant cumulative irradiation on TRAIL-induced apoptosis. Methods and Materials: Using a previously established HN3 cell line from a laryngeal carcinoma patient, we generated a chronically irradiated HN3R isogenic cell line. Viability and apoptosis in HN3 and HN3R cells treated with TRAIL were analyzed with MTS and PI/annexin V-FITC assays. Western blotting and flow cytometry were used to determine the underlying mechanism of TRAIL resistance. DR4 expression was semiquantitatively scored in a tissue microarray with 107 laryngeal cancer specimens. Methylation-specific polymerase chain reaction and bisulfite sequencing for DR4 were performed for genomic DNA isolated from each cell line. Results: HN3R cells were more resistant than HN3 cells to TRAIL-induced apoptosis because of significantly reduced levels of the DR4 receptor. The DR4 staining score in 37 salvage surgical specimens after radiation failure was lower in 70 surgical specimens without radiation treatment (3.03 ± 2.75 vs 5.46 ± 3.30, respectively; P<.001). HN3R cells had a methylated DR4 CpG island that was partially demethylated by the DNA demethylating agent 5-aza-2′-deoxycytidine. Conclusion: Epigenetic silencing of the TRAIL receptor by hypermethylation of a DR4 CpG island might be an underlying mechanism for TRAIL resistance in recurrent laryngeal carcinoma treated with radiation

Glioma CpG island methylator phenotype (G-CIMP): biological and clinical implications.

Science.gov (United States)

Malta, Tathiane M; de Souza, Camila F; Sabedot, Thais S; Silva, Tiago C; Mosella, Maritza S; Kalkanis, Steven N; Snyder, James; Castro, Ana Valeria B; Noushmehr, Houtan

2018-04-09

Gliomas are a heterogeneous group of brain tumors with distinct biological and clinical properties. Despite advances in surgical techniques and clinical regimens, treatment of high-grade glioma remains challenging and carries dismal rates of therapeutic success and overall survival. Challenges include the molecular complexity of gliomas, as well as inconsistencies in histopathological grading, resulting in an inaccurate prediction of disease progression and failure in the use of standard therapy. The updated 2016 World Health Organization (WHO) classification of tumors of the central nervous system reflects a refinement of tumor diagnostics by integrating the genotypic and phenotypic features, thereby narrowing the defined subgroups. The new classification recommends molecular diagnosis of isocitrate dehydrogenase (IDH) mutational status in gliomas. IDH-mutant gliomas manifest the cytosine-phosphate-guanine (CpG) island methylator phenotype (G-CIMP). Notably, the recent identification of clinically relevant subsets of G-CIMP tumors (G-CIMP-high and G-CIMP-low) provides a further refinement in glioma classification that is independent of grade and histology. This scheme may be useful for predicting patient outcome and may be translated into effective therapeutic strategies tailored to each patient. In this review, we highlight the evolution of our understanding of the G-CIMP subsets and how recent advances in characterizing the genome and epigenome of gliomas may influence future basic and translational research.

Comparison of insight and clinical variables in homeless and non-homeless psychiatric inpatients in China.

Science.gov (United States)

Fu, Yan-Nan; Cao, Xiao-Lan; Hou, Cai-Lan; Ng, Chee H; Ungvari, Gabor S; Chiu, Helen F K; Lin, Yong-Qiang; Wang, Lihui; Zheng, Xiaocong; Jia, Fu-Jun; Xiang, Yu-Tao

2017-09-01

There are no published data on insight in homeless patients with psychiatric disorders in China. This study examined insight in homeless and non-homeless Chinese psychiatric inpatients in relation to demographic and clinical variables. A total of 278 homeless and 222 non-homeless inpatients matched in age and gender were included in the study. Demographic and clinical characteristics were collected based on a review of medical charts and a clinical interview with standardized instruments. Insight was evaluated with the Insight and Treatment Attitudes Questionnaire. Altogether 20.5% of homeless inpatients and 43.7% of the non-homeless controls had good insight. Compared with homeless inpatients with impaired insight, homeless inpatients with good insight had higher physical quality of life, longer duration of illness and less severe positive and negative symptoms. Impaired insight appeared more common in homeless psychiatric inpatients in China. Further studies should address the need for effective therapeutic interventions that promote homeless patients' insight. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

31 CFR 19.500 - What is the purpose of the Excluded Parties List System (EPLS)?

Science.gov (United States)

2010-07-01

... 31 Money and Finance: Treasury 1 2010-07-01 2010-07-01 false What is the purpose of the Excluded Parties List System (EPLS)? 19.500 Section 19.500 Money and Finance: Treasury Office of the Secretary of the Treasury GOVERNMENTWIDE DEBARMENT AND SUSPENSION (NONPROCUREMENT) Excluded Parties List System...

Alterations of the spindle checkpoint pathway in clinicopathologically aggressive CpG island methylator phenotype clear cell renal cell carcinomas.

Science.gov (United States)

Arai, Eri; Gotoh, Masahiro; Tian, Ying; Sakamoto, Hiromi; Ono, Masaya; Matsuda, Akio; Takahashi, Yoriko; Miyata, Sayaka; Totsuka, Hirohiko; Chiku, Suenori; Komiyama, Motokiyo; Fujimoto, Hiroyuki; Matsumoto, Kenji; Yamada, Tesshi; Yoshida, Teruhiko; Kanai, Yae

2015-12-01

CpG-island methylator phenotype (CIMP)-positive clear cell renal cell carcinomas (RCCs) are characterized by accumulation of DNA hypermethylation of CpG islands, clinicopathological aggressiveness and poor patient outcome. The aim of this study was to clarify the molecular pathways participating in CIMP-positive renal carcinogenesis. Genome (whole-exome and copy number), transcriptome and proteome (two-dimensional image converted analysis of liquid chromatography-mass spectrometry) analyses were performed using tissue specimens of 87 CIMP-negative and 14 CIMP-positive clear cell RCCs and corresponding specimens of non-cancerous renal cortex. Genes encoding microtubule-associated proteins, such as DNAH2, DNAH5, DNAH10, RP1 and HAUS8, showed a 10% or higher incidence of genetic aberrations (non-synonymous single-nucleotide mutations and insertions/deletions) in CIMP-positive RCCs, whereas CIMP-negative RCCs lacked distinct genetic characteristics. MetaCore pathway analysis of CIMP-positive RCCs revealed that alterations of mRNA or protein expression were significantly accumulated in six pathways, all participating in the spindle checkpoint, including the "The metaphase checkpoint (p = 1.427 × 10(-6))," "Role of Anaphase Promoting Complex in cell cycle regulation (p = 7.444 × 10(-6))" and "Spindle assembly and chromosome separation (p = 9.260 × 10(-6))" pathways. Quantitative RT-PCR analysis revealed that mRNA expression levels for genes included in such pathways, i.e., AURKA, AURKB, BIRC5, BUB1, CDC20, NEK2 and SPC25, were significantly higher in CIMP-positive than in CIMP-negative RCCs. All CIMP-positive RCCs showed overexpression of Aurora kinases, AURKA and AURKB, and this overexpression was mainly attributable to increased copy number. These data suggest that abnormalities of the spindle checkpoint pathway participate in CIMP-positive renal carcinogenesis, and that AURKA and AURKB may be potential therapeutic targets in more aggressive CIMP-positive RCCs. �

CpG Methylation Analysis of HPV16 in Laser Capture Microdissected Archival Tissue and Whole Tissue Sections from High Grade Anal Squamous Intraepithelial Lesions: A Potential Disease Biomarker.

Directory of Open Access Journals (Sweden)

Monica Molano

Full Text Available Incidence and mortality rates of anal cancer are increasing globally. More than 90% of anal squamous cell carcinomas (ASCC are associated with human papillomavirus (HPV. Studies on HPV-related anogenital lesions have shown that patterns of methylation of viral and cellular DNA targets could potentially be developed as disease biomarkers. Lesion-specific DNA isolated from formalin-fixed paraffin-embedded (FFPE tissues from existing or prospective patient cohorts may constitute a valuable resource for methylation analysis. However, low concentrations of DNA make these samples technically challenging to analyse using existing methods. We therefore set out to develop a sensitive and reproducible nested PCR-pyrosequencing based method to accurately quantify methylation at 10 CpG sites within the E2BS1, E2BS2,3,4 and Sp1 binding sites in the viral upstream regulatory region of HPV16 genome. Methylation analyses using primary and nested PCR-pyrosequencing on 52 FFPE tissue [26 paired whole tissue sections (WTS and laser capture microdissected (LCM tissues] from patients with anal squamous intraepithelial lesions was performed. Using nested PCR, methylation results were obtained for the E2BS1, E2BS2,3,4 and Sp1 binding sites in 86.4% of the WTS and 81.8% of the LCM samples. Methylation patterns were strongly correlated within median values of matched pairs of WTS and LCM sections, but overall methylation was higher in LCM samples at different CpG sites. High grade lesions showed low methylation levels in the E2BS1 and E2BS2 regions, with increased methylation detected in the E2BS,3,4/Sp1 regions, showing the highest methylation at CpG site 37. The method developed is highly sensitive in samples with low amounts of DNA and demonstrated to be suitable for archival samples. Our data shows a possible role of specific methylation in the HPV16 URR for detection of HSIL.

Excluded volume effects caused by high concentration addition of acid generators in chemically amplified resists used for extreme ultraviolet lithography

Science.gov (United States)

Kozawa, Takahiro; Watanabe, Kyoko; Matsuoka, Kyoko; Yamamoto, Hiroki; Komuro, Yoshitaka; Kawana, Daisuke; Yamazaki, Akiyoshi

2017-08-01

The resolution of lithography used for the high-volume production of semiconductor devices has been improved to meet the market demands for highly integrated circuits. With the reduction in feature size, the molecular size becomes non-negligible in the resist material design. In this study, the excluded volume effects caused by adding high-concentration acid generators were investigated for triphenylsulfonium nonaflate. The resist film density was measured by X-ray diffractometry. The dependences of absorption coefficient and protected unit concentration on acid generator weight ratio were calculated from the measured film density. Using these values, the effects on the decomposition yield of acid generators, the protected unit fluctuation, and the line edge roughness (LER) were evaluated by simulation on the basis of sensitization and reaction mechanisms of chemically amplified extreme ultraviolet resists. The positive effects of the increase in acid generator weight ratio on LER were predominant below the acid generator weight ratio of 0.3, while the negative effects became equivalent to the positive effects above the acid generator weight ratio of 0.3 owing to the excluded volume effects.

Genome-wide CpG island methylation and intergenic demethylation propensities vary among different tumor sites.

Science.gov (United States)

Lee, Seung-Tae; Wiemels, Joseph L

2016-02-18

The epigenetic landscape of cancer includes both focal hypermethylation and broader hypomethylation in a genome-wide manner. By means of a comprehensive genomic analysis on 6637 tissues of 21 tumor types, we here show that the degrees of overall methylation in CpG island (CGI) and demethylation in intergenic regions, defined as 'backbone', largely vary among different tumors. Depending on tumor type, both CGI methylation and backbone demethylation are often associated with clinical, epidemiological and biological features such as age, sex, smoking history, anatomic location, histological type and grade, stage, molecular subtype and biological pathways. We found connections between CGI methylation and hypermutability, microsatellite instability, IDH1 mutation, 19p gain and polycomb features, and backbone demethylation with chromosomal instability, NSD1 and TP53 mutations, 5q and 19p loss and long repressive domains. These broad epigenetic patterns add a new dimension to our understanding of tumor biology and its clinical implications. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

Aberrant methylation of Polo-like kinase CpG islands in Plk4 heterozygous mice

International Nuclear Information System (INIS)

Ward, Alejandra; Morettin, Alan; Shum, David; Hudson, John W

2011-01-01

Hepatocellular carcinoma (HCC), one of the most common cancers world-wide occurs twice as often in men compared to women. Predisposing conditions such as alcoholism, chronic viral hepatitis, aflatoxin B1 ingestion, and cirrhosis all contribute to the development of HCC. We used a combination of methylation specific PCR and bisulfite sequencing, qReal-Time PCR (qPCR), and Western blot analysis to examine epigenetic changes for the Polo-like kinases (Plks) during the development of hepatocellular carcinoma (HCC) in Plk4 heterozygous mice and murine embryonic fibroblasts (MEFs). Here we report that the promoter methylation of Plk4 CpG islands increases with age, was more prevalent in males and that Plk4 epigenetic modification and subsequent downregulation of expression was associated with the development of HCC in Plk4 mutant mice. Interestingly, the opposite occurs with another Plk family member, Plk1 which was typically hypermethylated in normal liver tissue but became hypomethylated and upregulated in liver tumours. Furthermore, upon alcohol exposure murine embryonic fibroblasts exhibited increased Plk4 hypermethylation and downregulation along with increased centrosome numbers and multinucleation. These results suggest that aberrant Plk methylation is correlated with the development of HCC in mice

Sigh rate and respiratory variability during mental load and sustained attention.

Science.gov (United States)

Vlemincx, Elke; Taelman, Joachim; De Peuter, Steven; Van Diest, Ilse; Van den Bergh, Omer

2011-01-01

Spontaneous breathing consists of substantial correlated variability: Parameters characterizing a breath are correlated with parameters characterizing previous and future breaths. On the basis of dynamic system theory, negative emotion states are predicted to reduce correlated variability whereas sustained attention is expected to reduce total respiratory variability. Both are predicted to evoke sighing. To test this, respiratory variability and sighing were assessed during a baseline, stressful mental arithmetic task, nonstressful sustained attention task, and recovery in between tasks. For respiration rate (excluding sighs), reduced total variability was found during the attention task, whereas correlated variation was reduced during mental load. Sigh rate increased during mental load and during recovery from the attention task. It is concluded that mental load and task-related attention show specific patterns in respiratory variability and sigh rate. Copyright © 2010 Society for Psychophysiological Research.

Comments on the variability of inherent bioelement contents of spruce needles

International Nuclear Information System (INIS)

Wyttenbach, A.; Tobler, L.; Bajo, S.

1991-01-01

Inherent needle contents are the relevant concentrations within the needle, excluding surface contaminations by aerosols. The error arising from the analysis of unwashed needles is quantified. For many elements it is the source of a large apparent variability. Spatial variability is discussed under the aspects of variability among trees within a plot and of variability among different plots. Both terms have implications as to the number of trees that should be sampled for the characterization of a plot. Variability with time is investigated by following the needle concentrations from an age of 1 to 23 months. The results give indications on favourable sampling dates and on the physiology of the different elements. All investigations refer to 20 elements, which have been determined by neutron activation analysis. (author) 6 figs., 5 tabs., 16 refs

Actigraphy Detects Greater Intra-Individual Variability During Gait in Non-Manifesting LRRK2 Mutation Carriers.

Science.gov (United States)

van den Heuvel, Lieneke; Lim, Andrew S; Visanji, Naomi P; Huang, Jana; Ghate, Taneera; Mestre, Tiago A; AlDakheel, Amaal; Connolly, Barbara S; Gasca-Salas, Carmen; Kern, Drew S; Jain, Jennifer; Slow, Elizabeth J; Pondal, Margarita; Faust-Socher, Achinoam; Rogaeva, Ekaterina; Tomlinson, George; Lang, Anthony E; Marras, Connie

2018-01-01

With recent advances in the search for disease-modifying therapies for Parkinson's disease (PD) the importance of identifying prodromal markers becomes greater. Non-manifesting LRRK2 mutation carriers (NMC) are at risk for developing PD, and provide a population in which to identify possible markers. The aim of this study was to test the hypothesis that NMC have differences in daily activity, fragmentation of sleep, arm swing asymmetry, and movement variability during walking, detectable by actigraphy, as compared to matched control subjects. Eleven NMC, fourteen PD patients (4 LRRK2-PD, 10 idiopathic PD (iPD)), and twenty-nine controls wore wristbands containing an accelerometer for seven days, and performed a daily walking task. Outcome measures included daily activity, fragmentation of activity, fragmentation of sleep, arm swing asymmetry during walking, and intra-individual variability. Compared to healthy controls, both NMC and LRRK2/iPD showed higher intra-individual variability in activity during walking compared to healthy controls. Individuals with LRRK2-PD/iPD, but not NMC, tend to have lower activity levels, more arm swing asymmetry and less increase of arm swing with transition from slow to faster walking speed compared to healthy controls. Higher intra-individual variability of gait-associated movements might be a useful biomarker of prodromal PD. These results encourage replication in a larger sample and longitudinal analysis is warranted.

Combined effect of thermal dispersion and variable viscosity of non-darcy convection heat transfer in a fluidsaturated porous medium

KAUST Repository

El-Amin, Mohamed; Salama, Amgad; El-Amin, Ammaarah A.; Gorla, Rama Subba Reddy

2013-01-01

In this paper, the effects of thermal dispersion and variable viscosity on the non-Darcy free, mixed, and forced convection heat transfer along a vertical flat plate embedded in a fluid-saturated porous medium are investigated. Forchheimer extension

Identification of cadmium-excluding Welsh onion (Allium fistulosum L.) cultivars and their mechanisms of low cadmium accumulation.

Science.gov (United States)

Li, Xuhui; Zhou, Qixing; Wei, Shuhe; Ren, Wenjie

2012-06-01

Screening out cadmium (Cd) excluding cultivars of a crop in agricultural production is an effective way to prohibit Cd entering into food chain. A judging criterion for Cd-excluding cultivars based on food safety was suggested and used in the identification of Cd-excluding welsh onion (Allium fistulosum L.) cultivars. A pot culture experiment was carried out to screen out Cd-excluding cultivars, of which the results were confirmed by plot experiments. The relevant factors of Cd accumulation in the pseudostem were analyzed and used in the correlation analysis aiming to study the low Cd accumulation mechanisms. The concentration of Cd in the pseudostem of welsh onions was 0.08-0.20, 0.18-0.41, and 0.26-0.61 mg/kg fresh weight (FW) under three treatments (1.0, 2.5, and 5.0 mg/kg), respectively. The significant (p onion cultivars, but Cd contamination in soil had little influence on biomass and the contents of soluble sugar, NO(3)(-)-N, and eight other elements in the tested welsh onion cultivars. Two cultivars were identified as Cd-excluding cultivars, mainly because the accumulation of Cd in their pseudostem was only 0.041 ± 0.003 and 0.046 ± 0.002 mg/kg FW, and 0.054 ± 0.001 and 0.066 ± 0.011 mg/kg FW, when growing in plots with Cd concentration of 0.49 and 0.99 mg/kg, respectively. Ribentiegancongwang and Wuyeqi could be identified as Cd-excluding cultivars. Low bioaccumulation factor of the roots was the main mechanism of Cd-excluding welsh onion cultivars.

Complete Chloroplast Genome of Pinus massoniana (Pinaceae): Gene Rearrangements, Loss of ndh Genes, and Short Inverted Repeats Contraction, Expansion.

Science.gov (United States)

Ni, ZhouXian; Ye, YouJu; Bai, Tiandao; Xu, Meng; Xu, Li-An

2017-09-11

The chloroplast genome (CPG) of Pinus massoniana belonging to the genus Pinus (Pinaceae), which is a primary source of turpentine, was sequenced and analyzed in terms of gene rearrangements, ndh genes loss, and the contraction and expansion of short inverted repeats (IRs). P. massoniana CPG has a typical quadripartite structure that includes large single copy (LSC) (65,563 bp), small single copy (SSC) (53,230 bp) and two IRs (IRa and IRb, 485 bp). The 108 unique genes were identified, including 73 protein-coding genes, 31 tRNAs, and 4 rRNAs. Most of the 81 simple sequence repeats (SSRs) identified in CPG were mononucleotides motifs of A/T types and located in non-coding regions. Comparisons with related species revealed an inversion (21,556 bp) in the LSC region; P. massoniana CPG lacks all 11 intact ndh genes (four ndh genes lost completely; the five remained truncated as pseudogenes; and the other two ndh genes remain as pseudogenes because of short insertions or deletions). A pair of short IRs was found instead of large IRs, and size variations among pine species were observed, which resulted from short insertions or deletions and non-synchronized variations between "IRa" and "IRb". The results of phylogenetic analyses based on whole CPG sequences of 16 conifers indicated that the whole CPG sequences could be used as a powerful tool in phylogenetic analyses.

Lack of chart reminder effectiveness on family medicine resident JNC-VI and NCEP III guideline knowledge and attitudes

Directory of Open Access Journals (Sweden)

Upshur Ross EG

2004-07-01

should be considered for further investigation. The interpretation of CPG non-compliance will benefit from a causal matrix focused on physician knowledge, attitudes, and behavior. Recent findings in resident knowledge-behavior discordance may direct the future investigation of physician CPG non-compliance away from generalized barrier research, and toward the development of information that maximizes the sense of individual practitioner urgency and certainty.

PLS-based and regularization-based methods for the selection of relevant variables in non-targeted metabolomics data

Directory of Open Access Journals (Sweden)

Renata Bujak

2016-07-01

Full Text Available Non-targeted metabolomics constitutes a part of systems biology and aims to determine many metabolites in complex biological samples. Datasets obtained in non-targeted metabolomics studies are multivariate and high-dimensional due to the sensitivity of mass spectrometry-based detection methods as well as complexity of biological matrices. Proper selection of variables which contribute into group classification is a crucial step, especially in metabolomics studies which are focused on searching for disease biomarker candidates. In the present study, three different statistical approaches were tested using two metabolomics datasets (RH and PH study. Orthogonal projections to latent structures-discriminant analysis (OPLS-DA without and with multiple testing correction as well as least absolute shrinkage and selection operator (LASSO were tested and compared. For the RH study, OPLS-DA model built without multiple testing correction, selected 46 and 218 variables based on VIP criteria using Pareto and UV scaling, respectively. In the case of the PH study, 217 and 320 variables were selected based on VIP criteria using Pareto and UV scaling, respectively. In the RH study, OPLS-DA model built with multiple testing correction, selected 4 and 19 variables as statistically significant in terms of Pareto and UV scaling, respectively. For PH study, 14 and 18 variables were selected based on VIP criteria in terms of Pareto and UV scaling, respectively. Additionally, the concept and fundaments of the least absolute shrinkage and selection operator (LASSO with bootstrap procedure evaluating reproducibility of results, was demonstrated. In the RH and PH study, the LASSO selected 14 and 4 variables with reproducibility between 99.3% and 100%. However, apart from the popularity of PLS-DA and OPLS-DA methods in metabolomics, it should be highlighted that they do not control type I or type II error, but only arbitrarily establish a cut-off value for PLS-DA loadings

Hepatitis B surface antigen (HBsAg) and core antigen (HBcAg) combine CpG oligodeoxynucletides as a novel therapeutic vaccine for chronic hepatitis B infection.

Science.gov (United States)

Li, Jianqiang; Ge, Jun; Ren, Sulin; Zhou, Tong; Sun, Ying; Sun, Honglin; Gu, Yue; Huang, Hongying; Xu, Zhenxing; Chen, Xiaoxiao; Xu, Xiaowei; Zhuang, Xiaoqian; Song, Cuiling; Jia, Fangmiao; Xu, Aiguo; Yin, Xiaojin; Du, Sean X

2015-08-20

Hepatitis B virus infection is a non-cytopathic hepatotropic virus which can lead to chronic liver disease and hepatocellular carcinoma. Traditional therapies fail to provide sustained control of viral replication and liver damage in most patients. As an alternative strategy, immunotherapeutic approaches have shown promising efficacy in the treatment of chronic hepatitis B patients. Here, we investigated the efficacy of a novel therapeutic vaccine formulation consisting of two HBV antigens, HBsAg and HBcAg, and CpG adjuvant. This vaccine formulation elicits forceful humoral responses directed against HBsAg/HBcAg, and promotes a Th1/Th2 balance response against HBsAg and a Th1-biased response against HBcAg in both C57BL/6 and HBV transgenic mice. Vigorous cellular immune response was also detected in HBV transgenic mice, for a significantly higher number of HBs/HBc-specific IFN-γ secreting CD4+ and CD8+ T cells was generated. Moreover, vaccinated mice elicited significantly intense in vivo CTL attack, reduced serum HBsAg level without causing liver damage in HBV transgenic mice. In summary, this study demonstrates a novel therapeutic vaccine with the potential to elicit vigorous humoral and cellular response, overcoming tolerance in HBV transgenic mice. Copyright © 2015 Elsevier Ltd. All rights reserved.

Behavioral Variables Associated with Obesity in Police Officers

Science.gov (United States)

CAN, S. Hakan; HENDY, Helen M.

2014-01-01

Past research has documented that non-behavioral variables (such as long work hours, exposure to police stressors) are associated with obesity risk in police officers, but limited research has examined behavioral variables that might be targeted by Employee Assistance Programs for police weight management. The present study compared non-obese and obese officers for behavioral variables found associated with obesity in other adult samples: physical activity (cardiovascular, strength-training, stretching), sleep duration, and consumption of alcohol, fruit and vegetables, and snack foods. Participants included 172 male police officers who completed questionnaires to report height and weight, used to calculate body mass index (BMI = kg/m2) and to divide them into “non-obese” and “obese” groups. They also reported the above behaviors and six non-behavioral variables found associated with obesity risk: age, health problems, family support, police work hours, police stressors, police support. ANCOVAs compared each behavioral variable across obesity status (non-obese, obese), with the six non-behavioral variables used as covariates. Results revealed that cardiovascular and strength-training physical activity were the only behavioral variables that differed significantly between non-obese and obese police officers. The use of self-reported height and weight values may provide Employee Assistance Program with improved cost, time, and officer participation. PMID:24694574

Genome-wide DNA methylation profiling identifies ALDH1A3 promoter methylation as a prognostic predictor in G-CIMP- primary glioblastoma.

Science.gov (United States)

Zhang, Wei; Yan, Wei; You, Gan; Bao, Zhaoshi; Wang, Yongzhi; Liu, Yanwei; You, Yongping; Jiang, Tao

2013-01-01

To date, the aberrations in the DNA methylation patterns that are associated with different prognoses of G-CIMP- primary GBMs remain to be elucidated. Here, DNA methylation profiling of primary GBM tissues from 13 long-term survivors (LTS; overall survival ⩾18months) and 20 short-term survivors (STS; overall survival ⩽9months) was performed. Then G-CIMP+ samples were excluded. The differentially expressed CpG loci were identified between residual 18 STS and 9 LTS G-CIMP- samples. Methylation levels of 11 CpG loci (10genes) were statistically significantly lower, and 43 CpG loci (40genes) were statistically significantly higher in the tumor tissues of LTS than those of STS G-CIMP- samples (PCIMP- samples, 3 CpG loci localized in the promoter of ALDH1A3. Furthermore, using an independent validation cohort containing 37 primary GBM samples without IDH1 mutation and MGMT promoter methylation, the hypermethylation status of ALDH1A3 promoter predicted a better prognosis with an accompanied low expression of ALDH1A3 protein. Taken together, our results defined prognosis-related methylation signatures systematically for the first time in G-CIMP- primary GBMs. ALDH1A3 promoter methylation conferred a favorable prognosis in G-CIMP- primary GBMs. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Photoplethysmography pulse rate variability as a surrogate measurement of heart rate variability during non-stationary conditions

International Nuclear Information System (INIS)

Gil, E; Orini, M; Bailón, R; Laguna, P; Vergara, J M; Mainardi, L

2010-01-01

In this paper we assessed the possibility of using the pulse rate variability (PRV) extracted from the photoplethysmography signal as an alternative measurement of the HRV signal in non-stationary conditions. The study is based on analysis of the changes observed during a tilt table test in the heart rate modulation of 17 young subjects. First, the classical indices of HRV analysis were compared to the indices from PRV in intervals where stationarity was assumed. Second, the time-varying spectral properties of both signals were compared by time-frequency (TF) and TF coherence analysis. Third, the effect of replacing PRV with HRV in the assessment of the changes of the autonomic modulation of the heart rate was considered. Time-invariant HRV and PRV indices showed no statistically significant differences (p > 0.05) and high correlation (>0.97). Time-frequency analysis revealed that the TF spectra of both signals were highly correlated (0.99 ± 0.01); the difference between the instantaneous power, in the LF and HF bands, obtained from HRV and PRV was small (<10 −3 s −2 ) and their temporal patterns were highly correlated (0.98 ± 0.04 and 0.95 ± 0.06 in the LF and HF bands, respectively) and TF coherence in the LF and HF bands was high (0.97 ± 0.04 and 0.89 ± 0.08, respectively). Finally, the instantaneous power in the LF band was observed to significantly increase during head-up tilt by both HRV and PRV analysis. These results suggest that although some differences in the time-varying spectral indices extracted from HRV and PRV exist, mainly in the HF band associated with respiration, PRV could be used as a surrogate of HRV during non-stationary conditions, at least during the tilt table test

Multiplex protein pattern unmixing using a non-linear variable-weighted support vector machine as optimized by a particle swarm optimization algorithm.

Science.gov (United States)

Yang, Qin; Zou, Hong-Yan; Zhang, Yan; Tang, Li-Juan; Shen, Guo-Li; Jiang, Jian-Hui; Yu, Ru-Qin

2016-01-15

Most of the proteins locate more than one organelle in a cell. Unmixing the localization patterns of proteins is critical for understanding the protein functions and other vital cellular processes. Herein, non-linear machine learning technique is proposed for the first time upon protein pattern unmixing. Variable-weighted support vector machine (VW-SVM) is a demonstrated robust modeling technique with flexible and rational variable selection. As optimized by a global stochastic optimization technique, particle swarm optimization (PSO) algorithm, it makes VW-SVM to be an adaptive parameter-free method for automated unmixing of protein subcellular patterns. Results obtained by pattern unmixing of a set of fluorescence microscope images of cells indicate VW-SVM as optimized by PSO is able to extract useful pattern features by optimally rescaling each variable for non-linear SVM modeling, consequently leading to improved performances in multiplex protein pattern unmixing compared with conventional SVM and other exiting pattern unmixing methods. Copyright © 2015 Elsevier B.V. All rights reserved.

Oxytocin biases men but not women to restore social connections with individuals who socially exclude them.

Science.gov (United States)

Xu, Xiaolei; Yao, Shuxia; Xu, Lei; Geng, Yayuan; Zhao, Weihua; Ma, Xiaole; Kou, Juan; Luo, Ruixue; Kendrick, Keith M

2017-01-12

We normally react to individuals who exclude us socially by either avoiding them or increasing our attempts to interact with them. The neuropeptide oxytocin can promote social bonds and reduce social conflict and we therefore investigated whether it facilitates more positive social responses towards individuals who exclude or include us. In a double-blind, placebo-controlled, between-subject design 77 healthy Chinese male and female participants received intranasal oxytocin (40 IU) or placebo before playing a modified virtual ball-tossing game with three fictitious partners who either showed exclusion, inclusion or neutral behavioral interactions with them. Results showed that both male and female subjects threw the ball more often to individuals who excluded rather than included them, although oxytocin did not alter this or awareness/feelings of exclusion or inclusion. However, when subjects returned a week later males, but not females, in the oxytocin group exhibited an increased liking for, and preference for playing again with, players who had previously excluded them. This oxytocin effect was positively associated with independent traits. Our findings suggest that in a collectivist culture oxytocin may promote the desire of males, but not females, with a stronger independent orientation to rebuild social connections with individuals who have previously excluded them.

Heterogeneity of Prognostic Profiles in Non-small Cell Lung Cancer: Too Many Variables but a Few Relevant

International Nuclear Information System (INIS)

Camara, Agustin Gomez de la; Lopez-Encuentra, Angel; Ferrando, Paloma

2005-01-01

Objective: Many prognostic factors, exceeding 150, for non-small cell lung cancer (NSCLC) are mentioned in the literature. The different statistical weight of the some variables at issue, their heterogeneity and their clinical uselessness is reviewed. Study design and setting: Survival analysis of a cohort of NSCLC operated (n = 1730, 1993-1997) was carried out utilizing different statistical approaches: Cox proportional hazard analysis (CPHA), logistic regression (LRA), and recursive partitioning (CART). Results: CPHA identified 13 prognostic variables and 11 LRA. Of the 17 possible variables, 10 are coincident. CART provided five different diagnostic groups but only three differentiated survival levels. Parsimonious models were constructed including only T and N cancer staging variables. Areas under the ROC curve of 0.68 and 0.68 were found for CPHA and LGA parsimonious models respectively, and 0.72 and 0.71 for complete models. Conclusion: Variables with a minimal impact on the respective models and thus with little or scarce predictive clinical repercussion were identified. Differences in the prognostic profile of survival can be caused by the different methodological approaches used. No relevant differences were found between the parsimonious and complete models. Although the amount of information managed is considerable, there continues to be a large predictive gap yet to be explained

Non-stationarities significantly distort short-term spectral, symbolic and entropy heart rate variability indices

International Nuclear Information System (INIS)

Magagnin, Valentina; Bassani, Tito; Bari, Vlasta; Turiel, Maurizio; Porta, Alberto; Maestri, Roberto; Pinna, Gian Domenico

2011-01-01

The autonomic regulation is non-invasively estimated from heart rate variability (HRV). Many methods utilized to assess autonomic regulation require stationarity of HRV recordings. However, non-stationarities are frequently present even during well-controlled experiments, thus potentially biasing HRV indices. The aim of our study is to quantify the potential bias of spectral, symbolic and entropy HRV indices due to non-stationarities. We analyzed HRV series recorded in healthy subjects during uncontrolled daily life activities typical of 24 h Holter recordings and during predetermined levels of robotic-assisted treadmill-based physical exercise. A stationarity test checking the stability of the mean and variance over short HRV series (about 300 cardiac beats) was utilized to distinguish stationary periods from non-stationary ones. Spectral, symbolic and entropy indices evaluated solely over stationary periods were contrasted with those derived from all the HRV segments. When indices were calculated solely over stationary series, we found that (i) during both uncontrolled daily life activities and controlled physical exercise, the entropy-based complexity indices were significantly larger; (ii) during uncontrolled daily life activities, the spectral and symbolic indices linked to sympathetic modulation were significantly smaller and those associated with vagal modulation were significantly larger; (iii) while during uncontrolled daily life activities, the variance of spectral, symbolic and entropy rate indices was significantly larger, during controlled physical exercise, it was smaller. The study suggests that non-stationarities increase the likelihood to overestimate the contribution of sympathetic control and affect the power of statistical tests utilized to discriminate conditions and/or groups

Probable Chemical Hypoxia Effects on Progress of CNV Through Induction of Promoter CpG Demethylation and Overexpression of IL17RC in Human RPE Cells.

Science.gov (United States)

Alivand, Mohammad Reza; Sabouni, Farzaneh; Soheili, Zahra-Soheila

2016-09-01

To survey the changes of promoter CpG methylation status and mRNA expression of IL17RC (interleukin 17 receptor C) gene in retinal pigment epithelium (RPE) cells under chemical hypoxia condition for choroidal neovascularization (CNV) modeling in vitro. RPE cells were cultured in both untreated as a control group and treated by cobalt chloride media as a hypoxia group for various concentrations (100-150μM) and times (24-36 hrs.) To confirm chemical hypoxia condition, mRNA expression of HIF (Hypoxia Inducible Factor) -1α, -2α, and Vascular Endothelial Growth Factor (VEGF) was compared between two groups by Real-time PCR. Also, in normoxia and hypoxia conditions, IL17RC expression changes and promoter CpG methylation status were evaluated by Real-time PCR and methylation-specific PCR (MSP) techniques, respectively. Overexpression of HIF-1α, HIF-2α, and VEGF was significant in hypoxia versus normoxia conditions. Our data showed overexpression of IL17RC (2.1- to 6.3-fold) and decreasing of its promoter methylation in comparison with hypoxia and normoxia conditions. It was found that there are significant association between promoter methylation status and expression of IL17RC in chemical hypoxia condition. Therefore, methylation of IL17RC could play as a marker in CNV and degeneration of RPE cells in vitro. Additionally, HIF-α and methylation phenomena may be considered as critical targets for blocking in angiogenesis of age-related degeneration in future studies.

NNDSS - Table II. Salmonellosis (excluding typhoid fever and paratyphoid fever) to Shigellosis

Data.gov (United States)

U.S. Department of Health & Human Services — NNDSS - Table II. Salmonellosis (excluding typhoid fever and paratyphoid fever) to Shigellosis - 2018. In this Table, provisional cases of selected notifiable...

Cortical Contribution to Linear, Non-linear and Frequency Components of Motor Variability Control during Standing.

Science.gov (United States)

König Ignasiak, Niklas; Habermacher, Lars; Taylor, William R; Singh, Navrag B

2017-01-01

Motor variability is an inherent feature of all human movements and reflects the quality of functional task performance. Depending on the requirements of the motor task, the human sensory-motor system is thought to be able to flexibly govern the appropriate level of variability. However, it remains unclear which neurophysiological structures are responsible for the control of motor variability. In this study, we tested the contribution of cortical cognitive resources on the control of motor variability (in this case postural sway) using a dual-task paradigm and furthermore observed potential changes in control strategy by evaluating Ia-afferent integration (H-reflex). Twenty healthy subjects were instructed to stand relaxed on a force plate with eyes open and closed, as well as while trying to minimize sway magnitude and performing a "subtracting-sevens" cognitive task. In total 25 linear and non-linear parameters were used to evaluate postural sway, which were combined using a Principal Components procedure. Neurophysiological response of Ia-afferent reflex loop was quantified using the Hoffman reflex. In order to assess the contribution of the H-reflex on the sway outcome in the different standing conditions multiple mixed-model ANCOVAs were performed. The results suggest that subjects were unable to further minimize their sway, despite actively focusing to do so. The dual-task had a destabilizing effect on PS, which could partly (by 4%) be counter-balanced by increasing reliance on Ia-afferent information. The effect of the dual-task was larger than the protective mechanism of increasing Ia-afferent information. We, therefore, conclude that cortical structures, as compared to peripheral reflex loops, play a dominant role in the control of motor variability.

Variability of breath condensate pH may contribute to the better understanding of non-allergic seasonal respiratory diseases

Science.gov (United States)

Kullmann, Tamás; Szipőcs, Annamária

2017-09-01

The seasonal variability of certain non-allergic respiratory diseases is not clearly understood. Analysis of the breath condensate, the liquid that can be collected by breathing into a cold tube, has been proposed to bring closer to the understanding of airway pathologies. It has been assumed, that (1) airway lining fluid was a stable body liquid and (2) the breath condensate samples were representative of the airway lining fluid. Research was focussed on the identification of biomarkers indicative of respiratory pathologies. Despite 30 years of extended investigations breath condensate analysis has not gained any clinical implementation so far. The pH of the condensate is the characteristic that can be determined with the highest reproducibility. The present paper shows, that contrary to the initial assumptions, breath condensate is not a representative of the airway lining fluid, and the airway lining fluid is not a stable body liquid. Condensate pH shows baseline variability and it is influenced by drinking and by the ambient temperature. The changes in condensate pH are linked to changes in airway lining fluid pH. The variability of airway lining fluid pH may explain seasonal incidence of certain non-allergic respiratory diseases such as the catching of a common cold and the increased incidence of COPD exacerbations and exercise-induced bronchoconstriction in cold periods.

A non-local variable for general relativity

International Nuclear Information System (INIS)

Kozameh, C.N.; Newman, E.T.

1983-01-01

The usual description of differential geometry and general relativity is in terms of local fields, e.g. the metric, the curvature tensor, etc, which satisfy local differential equations. The authors introduce a new non-local field (Z) from which the local fields can be derived. Basically Z, though it is non-local, should be thought of as a function on the bundle of null directions on a space-time. The program can be divided into two parts; first the authors want to show the geometric meaning of and the relationship between Z and the local field. Then they want to provide field equations (non-local) for Z which will be equivalent to the vacuum Einstein equations for the local field. (Auth.)

INCIDENCE OF VARIABLES NON DIRECTLY CONTROLLABLE BY THE EDUCATIONAL SYSTEM IN STUDENTS’ READING LITERACY IN PISA: A COMPARATIVE STUDY SPAIN-FINLAND

Directory of Open Access Journals (Sweden)

Esteban Vázquez Cano

2014-05-01

Full Text Available This comparative research between Spain and Finland examines the incidence of eight variables of PISA (2012 typologically grouped in three areas: family, internet use for reading activities, and availability of books at home in students’ results in reading literacy. Through a descriptive and quantitative methodology, we analyze the incidence of these eight variables in Finnish and Spanish students’ reading literacy. The results show that parents’ academic and professional level along with the type of book that is available at home are non-significant variables in the development of a high reading literacy; by contrast, the variable that measures Internet use at home for reading news has been highly significant. Finnish students duplicate the Spanish in this variable which increases in 30 points reading literacy results.

Integration of CpG-free DNA induces de novo methylation of CpG islands in pluripotent stem cells

KAUST Repository

Takahashi, Yuta

2017-05-05

CpG islands (CGIs) are primarily promoter-associated genomic regions and are mostly unmethylated within highly methylated mammalian genomes. The mechanisms by which CGIs are protected from de novo methylation remain elusive. Here we show that insertion of CpG-free DNA into targeted CGIs induces de novo methylation of the entire CGI in human pluripotent stem cells (PSCs). The methylation status is stably maintained even after CpG-free DNA removal, extensive passaging, and differentiation. By targeting the DNA mismatch repair gene MLH1 CGI, we could generate a PSC model of a cancer-related epimutation. Furthermore, we successfully corrected aberrant imprinting in induced PSCs derived from an Angelman syndrome patient. Our results provide insights into how CpG-free DNA induces de novo CGI methylation and broaden the application of targeted epigenome editing for a better understanding of human development and disease.

CpG oligodeoxynucleotides are a potent adjuvant for an inactivated polio vaccine produced from Sabin strains of poliovirus.

Science.gov (United States)

Yang, Chunting; Shi, Huiying; Zhou, Jun; Liang, Yanwen; Xu, Honglin

2009-11-05

Poliovirus transmission is controlled globally through world-wide use of a live attenuated oral polio vaccine (OPV). However, the imminence of global poliovirus eradication calls for a switch to the inactivated polio vaccine (IPV). Given the limited manufacturing capacity and high cost of IPV, this switch is unlikely in most developing and undeveloped countries. Adjuvantation is an effective strategy for antigen sparing. In this study, we evaluated the adjuvanticity of CpG oligodeoxynucleotides (CpG-ODN) for an experimental IPV produced from Sabin strains of poliovirus. Our results showed that CpG-ODN, alone or in combination with alum, can significantly enhance both the humoral and cellular immune responses to IPV in mice, and, consequently, the antigen dose could be reduced substantially. Therefore, our study suggests that the global use of IPV could be facilitated by using CpG-ODN or other feasible adjuvants.

Only MR can safely exclude patients from arthroscopy

International Nuclear Information System (INIS)

Vincken, Patrice W.J.; Braak, Bert P.M. ter; Erkel, Arian R. van; Bloem, Johan L.; Bloem, Rolf M.; Luijt, Peter A. van; Coene, L.N.J.E.M.; Lange, Sam de

2009-01-01

The aim of this study was to determine in patients with subacute knee complaints and normal standardized physical examination the fraction of magnetic resonance imaging (MRI) studies showing arthroscopically treatable intra-articular pathology. There were 290 consecutive patients (between 16 and 45 years) with at least 4 weeks of knee complaints and low clinical suspicion of intra-articular pathology based on physical exam. Two hundred seventy-four patients were included. Sixteen patients with prior knee surgery, rheumatic arthritis, or severe osteoarthritis were excluded. MRI was used to assign patients to group 1 (treatable abnormalities) or group 2 (normal or no treatable findings), depending on whether MR demonstrated treatable pathology. Arthroscopy was performed in group 1 patients. If symptoms persisted for 3 months in group 2 patients, cross over to arthroscopy was allowed. MR showed treatable pathology in 73 patients (26.6%). Arthroscopy was performed in 64 patients of 73 patients (group 1). In 52 patients (81.3%, 95% confidence interval (CI) 71.4-91.1%), arthroscopy was therapeutic. Of the 13 arthroscopies (6.5%) in group 2, four were therapeutic (30.8%, 95% CI 1.7-59.8). The highest fraction of MR studies showing treatable pathology was found in males, aged over 30 years, with a history of effusion (54.5%, six of 11 patients). Authors believe that the negative predictive value of clinical assessment in patients with subacute knee complaints is too low to exclude these patients from MR. MR should at least be considered in male patients aged 30 years and over with a history of effusion. (orig.)

Only MR can safely exclude patients from arthroscopy

Energy Technology Data Exchange (ETDEWEB)

Vincken, Patrice W.J.; Braak, Bert P.M. ter; Erkel, Arian R. van; Bloem, Johan L. [Leiden University Medical Center, Department of Radiology, P.O. Box 9600, Leiden (Netherlands); Bloem, Rolf M. [Leiden University Medical Center, Department of Orthopedic Surgery, Leiden (Netherlands); Reinier de Graaf Gasthuis, Department of Orthopedic Surgery, Delft (Netherlands); Luijt, Peter A. van [Leiden University Medical Center, Department of Traumatology, Leiden (Netherlands); Coene, L.N.J.E.M. [HAGA Hospital, Department of Orthopaedic Surgery, The Hague (Netherlands); Lange, Sam de [Medical Center Haaglanden, Department of Orthopedic Surgery, The Hague (Netherlands)

2009-10-15

The aim of this study was to determine in patients with subacute knee complaints and normal standardized physical examination the fraction of magnetic resonance imaging (MRI) studies showing arthroscopically treatable intra-articular pathology. There were 290 consecutive patients (between 16 and 45 years) with at least 4 weeks of knee complaints and low clinical suspicion of intra-articular pathology based on physical exam. Two hundred seventy-four patients were included. Sixteen patients with prior knee surgery, rheumatic arthritis, or severe osteoarthritis were excluded. MRI was used to assign patients to group 1 (treatable abnormalities) or group 2 (normal or no treatable findings), depending on whether MR demonstrated treatable pathology. Arthroscopy was performed in group 1 patients. If symptoms persisted for 3 months in group 2 patients, cross over to arthroscopy was allowed. MR showed treatable pathology in 73 patients (26.6%). Arthroscopy was performed in 64 patients of 73 patients (group 1). In 52 patients (81.3%, 95% confidence interval (CI) 71.4-91.1%), arthroscopy was therapeutic. Of the 13 arthroscopies (6.5%) in group 2, four were therapeutic (30.8%, 95% CI 1.7-59.8). The highest fraction of MR studies showing treatable pathology was found in males, aged over 30 years, with a history of effusion (54.5%, six of 11 patients). Authors believe that the negative predictive value of clinical assessment in patients with subacute knee complaints is too low to exclude these patients from MR. MR should at least be considered in male patients aged 30 years and over with a history of effusion. (orig.)

Thermoelastic analysis of non-uniform pressurized functionally graded cylinder with variable thickness using first order shear deformation theory(FSDT) and perturbation method

Science.gov (United States)

Khoshgoftar, M. J.; Mirzaali, M. J.; Rahimi, G. H.

2015-11-01

Recently application of functionally graded materials(FGMs) have attracted a great deal of interest. These materials are composed of various materials with different micro-structures which can vary spatially in FGMs. Such composites with varying thickness and non-uniform pressure can be used in the aerospace engineering. Therefore, analysis of such composite is of high importance in engineering problems. Thermoelastic analysis of functionally graded cylinder with variable thickness under non-uniform pressure is considered. First order shear deformation theory and total potential energy approach is applied to obtain the governing equations of non-homogeneous cylinder. Considering the inner and outer solutions, perturbation series are applied to solve the governing equations. Outer solution for out of boundaries and more sensitive variable in inner solution at the boundaries are considered. Combining of inner and outer solution for near and far points from boundaries leads to high accurate displacement field distribution. The main aim of this paper is to show the capability of matched asymptotic solution for different non-homogeneous cylinders with different shapes and different non-uniform pressures. The results can be used to design the optimum thickness of the cylinder and also some properties such as high temperature residence by applying non-homogeneous material.

Psychiatric Disorder or Impairing Psychology in Children Who Have Been Excluded from School: A Systematic Review

Science.gov (United States)

Whear, Rebecca; Marlow, Ruth; Boddy, Kate; Ukoumunne, Obioha C.; Parker, Claire; Ford, Tamsin; Thompson-Coon, Jo; Stein, Ken

2014-01-01

When children with special educational needs are excluded from school, it should raise the concern that these children are not receiving adequate help and support. This systematic review aims to identify the prevalence of psychiatric disorder or impairing psychopathology among children who are excluded from school compared to children who are not…

Non-linear indices of heart rate variability during endodontic treatment.

Science.gov (United States)

Santana, Milana Drumond Ramos; Pita Neto, Ivo Cavalcante; Martiniano, Eli Carlos; Monteiro, Larissa Raylane Lucas; Ramos, José Lucas Souza; Garner, David M; Valenti, Vitor Engácia; Abreu, Luiz Carlos de

2016-01-01

Dental treatment promotes psychosomatic change that can influence the procedure and compromise the general well-being of the patient. In this context, it highlights the importance of evaluating the function of the autonomic nervous system in individuals undergoing endodontic treatment. Thus, this manuscript aimed to analyse cardiac autonomic modulation, through non-linear indices of heart rate variability (HRV) during endodontic treatment. Analysis of 50 subjects of either sex aged between 18 and 40 years diagnosed with irreversible pulp necrosis of lower molars undergoing endodontic treatment was undertaken. We carried out fractal and symbolic analysis of HRV, which was recorded in the first session of the endodontic treatment at four intervals: T1: 0-10 min before the onset of the treatment session; T2: 0-10 min after the application of anaesthesia; T3: throughout the period of treatment; and T4: 0-30 min after the end of the treatment session. There was reduction of α1 in T2 compared to T1 and T4 (p endodontic treatment, and after applying local anaesthetic the parasympathetic component of HRV increases. These data indicate that endodontic treatment acutely overcharges the heart, supporting the stress involved in this situation.

A systematic search for linkage with nonsyndromic recessive deafness in two large Middle Eastern inbred kindreds excludes more than 30% of the genome

Energy Technology Data Exchange (ETDEWEB)

Weiss, S.; Korostishevsky, M. [Sackler Faculty of Medicine, Ramat-Aviv (Israel); Frydman, M. [Haim Sheba Medical Center, Tel-Hashomer (Israel)] [and others

1994-09-01

It has been estimated that as many as 35 loci may individually cause autosomal recessive non-syndromic deafness. The extreme genetic heterogeneity, limited clinical differentiation and phenotypic assortative mating in many western countries make many families unsuitable for genetic linkage studies. Recently the first of those loci was mapped (to 13q) in two consanguineous families from northern Tunisia. We are studying two large highly consanguineous Middle Eastern kindreds (a total of 26 deaf in 98 sampled individuals). Examination in each family showed no evidence of clinical heterogeneity and indicated an uncomplicated profound bilateral sensorineural deafness. We have been able to exclude the 13q locus as the cause of deafness in each kindred and have also excluded such `candidate` loci as regions as those causing Usher`s syndrome type 1 (11q13)(11p), Usher`s syndrome type II (1q32-q41), Waardenburg syndrome type I (2q37), branchio-oto-renal syndrome (8q12-q13), Monge`s deafness (5q31), and Treacher Collins syndrome (5q31.3-q33.3). To date, no lod scores greater than 1 have been obtained in either kindred using 150 RFLT`s, VNTR`s and highly polymorphic microsatellite markers (CA repeats and tetranucleotides). By Morton`s criterion a minimum of 30% of the autosomal genome can be excluded for each kindred separately.

Pathology of idiopathic non-cirrhotic portal hypertension.

Science.gov (United States)

Guido, Maria; Sarcognato, Samantha; Sacchi, Diana; Colloredo, Guido

2018-04-12

Idiopathic non-cirrhotic portal hypertension is an under-recognized vascular liver disease of unknown etiology, characterized by clinical signs of portal hypertension in the absence of cirrhosis. By definition, any disorder known to cause portal hypertension in the absence of cirrhosis and any cause of chronic liver disease must be excluded to make a diagnosis of idiopathic non-cirrhotic portal hypertension. However, the diagnosis is often difficult because the disease resembles cirrhosis and there is no gold standard test. Liver biopsy is an essential tool: it is able to exclude cirrhosis and other causes of portal hypertension and it allows the identification of the characteristic lesions. Nonetheless, the histological diagnosis of idiopathic non-cirrhotic portal hypertension is not always straightforward, in particular by needle biopsy samples, because there is no pathognomonic lesion, but rather a variety of vascular changes which are unevenly distributed, very subtle, and not all necessarily identified in a single specimen. Pathologists should be able to recognize several patterns of injury, involving portal/periportal areas as well as parenchymal structures.The histological features of idiopathic non-cirrhotic portal hypertension are described in this review, focusing on their interpretation in needle biopsy specimens.

Coil–globule transition of a polymer involved in excluded-volume interactions with macromolecules

International Nuclear Information System (INIS)

Odagiri, Kenta; Seki, Kazuhiko

2015-01-01

Polymers adopt extended coil and compact globule states according to the balance between entropy and interaction energies. The transition of a polymer between an extended coil state and compact globule state can be induced by changing thermodynamic force such as temperature to alter the energy/entropy balance. Previously, this transition was theoretically studied by taking into account the excluded-volume interaction between monomers of a polymer chain using the partition function. For binary mixtures of a long polymer and short polymers, the coil-globule transition can be induced by changing the concentration of the shorter polymers. Here, we investigate the transition caused by short polymers by generalizing the partition function of the long polymer to include the excluded-volume effect of short polymers. The coil-globule transition is studied as a function of the concentration of mixed polymers by systematically varying Flory’s χ-parameters. We show that the transition is caused by the interplay between the excluded-volume interaction and the dispersion state of short polymers in the solvent. We also reveal that the same results can be obtained by combining the mixing entropy and elastic energy if the volume of a long polymer is properly defined

Color pattern evolution in Vanessa butterflies (Nymphalidae: Nymphalini): non-eyespot characters.

Science.gov (United States)

Abbasi, Roohollah; Marcus, Jeffrey M

2015-01-01

A phylogenetic approach was used to study color pattern evolution in Vanessa butterflies. Twenty-four color pattern elements from the Nymphalid ground plan were identified on the dorsal and ventral surfaces of the fore- and hind wings. Eyespot characters were excluded and will be examined elsewhere. The evolution of each character was traced over a Bayesian phylogeny of Vanessa reconstructed from 7750 DNA base pairs from 10 genes. Generally, the correspondence between character states on the same surface of the two wings is stronger on the ventral side compared to the dorsal side. The evolution of character states on both sides of a wing correspond with each other in most extant species, but the correspondence between dorsal and ventral character states is much stronger in the forewing than in the hindwing. The dorsal hindwing of many species of Vanessa is covered with an extended Basal Symmetry System and the Discalis I pattern element is highly variable between species, making this wing surface dissimilar to the other wing surfaces. The Basal Symmetry System and Discalis I may contribute to behavioral thermoregulation in Vanessa. Overall, interspecific directional character state evolution of non-eyespot color patterns is relatively rare in Vanessa, with a majority of color pattern elements showing non-variable, non-directional, or ambiguous character state evolution. The ease with which the development of color patterns can be modified, including character state reversals, has likely made important contributions to the production of color pattern diversity in Vanessa and other butterfly groups. © 2014 Wiley Periodicals, Inc.

Environmental stress affects DNA methylation of a CpG rich promoter region of serotonin transporter gene in a nurse cohort.

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Jukka S Alasaari

Full Text Available Shift-working nurses are exposed to a stressful work environment, which puts them at an increased risk for burnout and depression. We explored the effect of environmental stress on serotonin transporter gene (SLC6A4 promoter methylation among nurses from high and low work stress environments.Using bisulfite sequencing, we investigated the methylation status of five CpG residues of a CpG-rich region in the promoter of SLC6A4 by comparing female shift working nurses from a high work stress environment (n = 24 to low work stress environment (n = 25. We also analyzed the association of 5-HTTLPR polymorphism at 5' end of SLC6A4. Work stress was assessed by the Karasek's Model and possible signs of burnout or depression were measured by the Maslach Burnout Index General Survey and Beck Depression Index. Methylation levels were assessed by bisulfite sequencing of DNA extracted from peripheral blood leucocytes. Restriction enzyme treatment followed by standard PCR was used to identify 5-HTTLPR genotypes.We found that nurses in the high stress environment had significantly lower promoter methylation levels at all five CpG residues compared to nurses in the low stress environment (p<0.01. There was no significant interaction of 5-HTTLPR genotype and work stress with methylation (p = 0.58. In unadjusted (bivariate analysis, burnout was not significantly associated to methylation levels. However, when mutually adjusted for both, burnout and work stress were significant contributors (p = 0.038 and p<0.0001 respectively to methylation levels.Our findings show that environmental stress is concurrent with decreased methylation of the SLC6A4 promoter. This may lead to increased transcriptional activity of the gene, increased reuptake of serotonin from synaptic clefts, and termination of the activity of serotonin. This could present a possible coping mechanism for environmental stress in humans that could eventually increase risk for disturbed functional

The application of methylation specific electrophoresis (MSE to DNA methylation analysis of the 5' CpG island of mucin in cancer cells

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Yokoyama Seiya

2012-02-01

Full Text Available Abstract Background Methylation of CpG sites in genomic DNA plays an important role in gene regulation and especially in gene silencing. We have reported mechanisms of epigenetic regulation for expression of mucins, which are markers of malignancy potential and early detection of human neoplasms. Epigenetic changes in promoter regions appear to be the first step in expression of mucins. Thus, detection of promoter methylation status is important for early diagnosis of cancer, monitoring of tumor behavior, and evaluating the response of tumors to targeted therapy. However, conventional analytical methods for DNA methylation require a large amount of DNA and have low sensitivity. Methods Here, we report a modified version of the bisulfite-DGGE (denaturing gradient gel electrophoresis using a nested PCR approach. We designated this method as methylation specific electrophoresis (MSE. The MSE method is comprised of the following steps: (a bisulfite treatment of genomic DNA, (b amplification of the target DNA by a nested PCR approach and (c applying to DGGE. To examine whether the MSE method is able to analyze DNA methylation of mucin genes in various samples, we apply it to DNA obtained from state cell lines, ethanol-fixed colonic crypts and human pancreatic juices. Result The MSE method greatly decreases the amount of input DNA. The lower detection limit for distinguishing different methylation status is Conclusions The MSE method can provide a qualitative information of methylated sequence profile. The MSE method allows sensitive and specific analysis of the DNA methylation pattern of almost any block of multiple CpG sites. The MSE method can be applied to analysis of DNA methylation status in many different clinical samples, and this may facilitate identification of new risk markers.

Non-manufacturing applications of robotics

International Nuclear Information System (INIS)

Dauchez, P.

2000-12-01

This book presents the different non-manufacturing sectors of activity where robotics can have useful or necessary applications: underwater robotics, agriculture robotics, road work robotics, nuclear robotics, medical-surgery robotics, aids to disabled people, entertainment robotics. Service robotics has been voluntarily excluded because this developing sector is not mature yet. (J.S.)

Short-term variability of binary and non-binary Trans-Neptunian Objects

Science.gov (United States)

Thirouin, Audrey; Noll, K. S.; Campo Bagatin, A.; Ortiz Moreno, J. L.; Morales, N.

2013-10-01

Since 1992, more than 1400 Trans-Neptunian Objects (TNOs) have been discovered. Our approach to understand such objects is to study their rotations by monitoring their brightness variations. By studying the rotational properties of the TNOs a wealth of information can be obtained on their physics. So, the study of the spins and shapes of TNOs is a powerful method of gaining information on the formation and evolution of our Solar System. We have observed most of the brightest TNOs and centaurs, and compiled one of the largest lightcurves samples. The main purpose was to increase the number of objects whose short-term variability has been studied and present a homogeneous dataset trying to avoid observational biases. A dataset composed of 54 TNOs/Centaurs is reported and analyzed. Amplitudes and rotational periods have been derived for 45 of them with different degrees of reliability. For 9 objects, only an estimation of the amplitude is reported. Because most of the TNOs/Centaurs have low amplitude lightcurves, it is difficult to distinguish between single- and double-peaked lightcurves. Based on our results and the literature, following Binzel et al. (1989) study about asteroids rotational frequency distribution, we studied the TNOs spin rate distributions. We performed several Maxwellian fits to various histograms obtained considering that the lightcurves are single- or double-peaked. We tested lightcurve amplitude limits to distinguish if the lightcurve is albedo- or shape-dominated. Such a consideration introduces important changes in the distribution. We derived that an amplitude limit of 0.15mag gave a good fit to Maxwellian distribution. So, it seems that 0.15mag is a good measure of the typical variability caused by albedo. We studied the short-term variability of binary TNOs thanks to unresolved lightcurves. Based on our results and those from the literature, we come up with a sample of 32 systems with a rotational period and/or lightcurve amplitude value

A terahertz EO detector with large dynamical range, high modulation depth and signal-noise ratio

Science.gov (United States)

Pan, Xinjian; Cai, Yi; Zeng, Xuanke; Zheng, Shuiqin; Li, Jingzhen; Xu, Shixiang

2017-05-01

The paper presents a novel design for terahertz (THz) free-space time domain electro-optic (EO) detection where the static birefringent phases of the two balanced arms are set close to zero but opposite to each other. Our theoretical and numerical analyses show this design has much stronger ability to cancel the optical background noise than both THz ellipsometer and traditional crossed polarizer geometry (CPG). Its optical modulation depth is about twice as high as that of traditional CPG, but about ten times as high as that of THz ellipsometer. As for the dynamical range, our improved design is comparable to the THz ellipsometer but obviously larger than the traditional CPG. Some experiments for comparing our improved CPG with traditional CPG agree well with the corresponding theoretical predictions. Our experiments also show that the splitting ratio of the used non-polarization beam splitter is critical for the performance of our design.

CpG oligodeoxynucleotides are effective in therapy of minimal residual tumour disease after chemotherapy or surgery in a murine model of MHC class I-deficient, HPV16-associated tumours

Czech Academy of Sciences Publication Activity Database

Reiniš, Milan; Šímová, Jana; Indrová, Marie; Bieblová, Jana; Bubeník, Jan

2007-01-01

Roč. 30, č. 5 (2007), s. 1247-1251 ISSN 1019-6439 R&D Projects: GA ČR GA301/04/0492; GA ČR GA301/06/0774 EU Projects: European Commission(XE) 18933 - CLINIGENE Grant - others:Liga proti rakovině, Praha(CZ) XX Institutional research plan: CEZ:AV0Z50520514 Keywords : HPV 16 * minimal residual tumour disease * CpG oligonucleotides Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.295, year: 2007

40 CFR 725.910 - Persons excluded from reporting significant new uses.

Science.gov (United States)

2010-07-01

... 40 Protection of Environment 30 2010-07-01 2010-07-01 false Persons excluded from reporting significant new uses. 725.910 Section 725.910 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY... designated significant new uses, or (2) That the recipient has knowledge of the specific section in subpart M...

An application of the variable-r method to subpopulation growth rates in a 19th century agricultural population

Directory of Open Access Journals (Sweden)

Corey Sparks

2009-07-01

Full Text Available This paper presents an analysis of the differential growth rates of the farming and non-farming segments of a rural Scottish community during the 19th and early 20th centuries using the variable-r method allowing for net migration. Using this method, I find that the farming population of Orkney, Scotland, showed less variability in their reproduction and growth rates than the non-farming population during a period of net population decline. I conclude by suggesting that the variable-r method can be used in general cases where the relative growth of subpopulations or subpopulation reproduction is of interest.

EG-05COMBINATION OF GENE COPY GAIN AND EPIGENETIC DEREGULATION ARE ASSOCIATED WITH THE ABERRANT EXPRESSION OF A STEM CELL RELATED HOX-SIGNATURE IN GLIOBLASTOMA

Science.gov (United States)

Kurscheid, Sebastian; Bady, Pierre; Sciuscio, Davide; Samarzija, Ivana; Shay, Tal; Vassallo, Irene; Van Criekinge, Wim; Domany, Eytan; Stupp, Roger; Delorenzi, Mauro; Hegi, Monika

2014-01-01

We previously reported a stem cell related HOX gene signature associated with resistance to chemo-radiotherapy (TMZ/RT- > TMZ) in glioblastoma. However, underlying mechanisms triggering overexpression remain mostly elusive. Interestingly, HOX genes are neither involved in the developing brain, nor expressed in normal brain, suggestive of an acquired gene expression signature during gliomagenesis. HOXA genes are located on CHR 7 that displays trisomy in most glioblastoma which strongly impacts gene expression on this chromosome, modulated by local regulatory elements. Furthermore we observed more pronounced DNA methylation across the HOXA locus as compared to non-tumoral brain (Human methylation 450K BeadChip Illumina; 59 glioblastoma, 5 non-tumoral brain sampes). CpG probes annotated for HOX-signature genes, contributing most to the variability, served as input into the analysis of DNA methylation and expression to identify key regulatory regions. The structural similarity of the observed correlation matrices between DNA methylation and gene expression in our cohort and an independent data-set from TCGA (106 glioblastoma) was remarkable (RV-coefficient, 0.84; p-value < 0.0001). We identified a CpG located in the promoter region of the HOXA10 locus exerting the strongest mean negative correlation between methylation and expression of the whole HOX-signature. Applying this analysis the same CpG emerged in the external set. We then determined the contribution of both, gene copy aberration (CNA) and methylation at the selected probe to explain expression of the HOX-signature using a linear model. Statistically significant results suggested an additive effect between gene dosage and methylation at the key CpG identified. Similarly, such an additive effect was also observed in the external data-set. Taken together, we hypothesize that overexpression of the stem-cell related HOX signature is triggered by gain of trisomy 7 and escape from compensatory DNA methylation at

Strand bias in complementary single-nucleotide polymorphisms of transcribed human sequences: evidence for functional effects of synonymous polymorphisms

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Majewski Jacek

2006-08-01

Full Text Available Abstract Background Complementary single-nucleotide polymorphisms (SNPs may not be distributed equally between two DNA strands if the strands are functionally distinct, such as in transcribed genes. In introns, an excess of A↔G over the complementary C↔T substitutions had previously been found and attributed to transcription-coupled repair (TCR, demonstrating the valuable functional clues that can be obtained by studying such asymmetry. Here we studied asymmetry of human synonymous SNPs (sSNPs in the fourfold degenerate (FFD sites as compared to intronic SNPs (iSNPs. Results The identities of the ancestral bases and the direction of mutations were inferred from human-chimpanzee genomic alignment. After correction for background nucleotide composition, excess of A→G over the complementary T→C polymorphisms, which was observed previously and can be explained by TCR, was confirmed in FFD SNPs and iSNPs. However, when SNPs were separately examined according to whether they mapped to a CpG dinucleotide or not, an excess of C→T over G→A polymorphisms was found in non-CpG site FFD SNPs but was absent from iSNPs and CpG site FFD SNPs. Conclusion The genome-wide discrepancy of human FFD SNPs provides novel evidence for widespread selective pressure due to functional effects of sSNPs. The similar asymmetry pattern of FFD SNPs and iSNPs that map to a CpG can be explained by transcription-coupled mechanisms, including TCR and transcription-coupled mutation. Because of the hypermutability of CpG sites, more CpG site FFD SNPs are relatively younger and have confronted less selection effect than non-CpG FFD SNPs, which can explain the asymmetric discrepancy of CpG site FFD SNPs vs. non-CpG site FFD SNPs.

The CpG island encompassing the promoter and first exon of human DNMT3L gene is a PcG/TrX response element (PRE).

Science.gov (United States)

Basu, Amitava; Dasari, Vasanthi; Mishra, Rakesh K; Khosla, Sanjeev

2014-01-01

DNMT3L, a member of DNA methyltransferases family, is present only in mammals. As it provides specificity to the action of de novo methyltransferases, DNMT3A and DNMT3B and interacts with histone H3, DNMT3L has been invoked as the molecule that can read the histone code and translate it into DNA methylation. It plays an important role in the initiation of genomic imprints during gametogenesis and in nuclear reprogramming. With important functions attributed to it, it is imperative that the DNMT3L expression is tightly controlled. Previously, we had identified a CpG island within the human DNMT3L promoter and first exon that showed loss of DNA methylation in cancer samples. Here we show that this Differentially Methylated CpG island within DNMT3L (DNMT3L DMC) acts to repress transcription, is a Polycomb/Trithorax Response Element (PRE) and interacts with both PRC1 and PRC2 Polycomb repressive complexes. In addition, it adopts inactive chromatin conformation and is associated with other inactive chromatin-specific proteins like SUV39H1 and HP1. The presence of DNMT3L DMC also influences the adjacent promoter to adopt repressive histone post-translational modifications. Due to its association with multiple layers of repressive epigenetic modifications, we believe that PRE within the DNMT3L DMC is responsible for the tight regulation of DNMT3L expression and the aberrant epigenetic modifications of this region leading to DNMT3L overexpression could be the reason of nuclear programming during carcinogenesis.

The CpG island encompassing the promoter and first exon of human DNMT3L gene is a PcG/TrX response element (PRE.

Directory of Open Access Journals (Sweden)

Amitava Basu

Full Text Available DNMT3L, a member of DNA methyltransferases family, is present only in mammals. As it provides specificity to the action of de novo methyltransferases, DNMT3A and DNMT3B and interacts with histone H3, DNMT3L has been invoked as the molecule that can read the histone code and translate it into DNA methylation. It plays an important role in the initiation of genomic imprints during gametogenesis and in nuclear reprogramming. With important functions attributed to it, it is imperative that the DNMT3L expression is tightly controlled. Previously, we had identified a CpG island within the human DNMT3L promoter and first exon that showed loss of DNA methylation in cancer samples. Here we show that this Differentially Methylated CpG island within DNMT3L (DNMT3L DMC acts to repress transcription, is a Polycomb/Trithorax Response Element (PRE and interacts with both PRC1 and PRC2 Polycomb repressive complexes. In addition, it adopts inactive chromatin conformation and is associated with other inactive chromatin-specific proteins like SUV39H1 and HP1. The presence of DNMT3L DMC also influences the adjacent promoter to adopt repressive histone post-translational modifications. Due to its association with multiple layers of repressive epigenetic modifications, we believe that PRE within the DNMT3L DMC is responsible for the tight regulation of DNMT3L expression and the aberrant epigenetic modifications of this region leading to DNMT3L overexpression could be the reason of nuclear programming during carcinogenesis.

Using non-systematic surveys to investigate effects of regional climate variability on Australasian gannets in the Hauraki Gulf, New Zealand

Science.gov (United States)

Srinivasan, Mridula; Dassis, Mariela; Benn, Emily; Stockin, Karen A.; Martinez, Emmanuelle; Machovsky-Capuska, Gabriel E.

2015-05-01

Few studies have investigated regional and natural climate variability on seabird populations using ocean reanalysis datasets (e.g. Simple Ocean Data Assimilation (SODA)) that integrate atmospheric information to supplement ocean observations and provide improved estimates of ocean conditions. Herein we use a non-systematic dataset on Australasian gannets (Morus serrator) from 2001 to 2009 to identify potential connections between Gannet Sightings Per Unit Effort (GSPUE) and climate and oceanographic variability in a region of known importance for breeding seabirds, the Hauraki Gulf (HG), New Zealand. While no statistically significant relationships between GSPUE and global climate indices were determined, there was a significant correlation between GSPUE and regional SST anomaly for HG. Also, there appears to be a strong link between global climate indices and regional climate in the HG. Further, based on cross-correlation function coefficients and lagged multiple regression models, we identified potential leading and lagging climate variables, and climate variables but with limited predictive capacity in forecasting future GSPUE. Despite significant inter-annual variability and marginally cooler SSTs since 2001, gannet sightings appear to be increasing. We hypothesize that at present underlying physical changes in the marine ecosystem may be insufficient to affect supply of preferred gannet main prey (pilchard Sardinops spp.), which tolerate a wide thermal range. Our study showcases the potential scientific value of lengthy non-systematic data streams and when designed properly (i.e., contain abundance, flock size, and spatial data), can yield useful information in climate impact studies on seabirds and other marine fauna. Such information can be invaluable for enhancing conservation measures for protected species in fiscally constrained research environments.

Distinct features between MLH1-methylated and unmethylated colorectal carcinomas with the CpG island methylator phenotype: implications in the serrated neoplasia pathway.

Science.gov (United States)

Kim, Jung Ho; Bae, Jeong Mo; Cho, Nam-Yun; Kang, Gyeong Hoon

2016-03-22

The presence or absence of MLH1 methylation may critically affect the heterogeneity of colorectal carcinoma (CRC) with the CpG island methylator phenotype (CIMP). Here, we investigated the differential characteristics of CIMP-high (CIMP-H) CRCs according to MLH1 methylation status. To further confirm the MLH1-dependent features in CIMP-H CRC, an independent analysis was performed using data from The Cancer Genome Atlas (TCGA). In our CIMP-H CRC samples, MLH1-methylated tumors were characterized by older patient age, proximal colonic location, mucinous histology, intense lymphoid reactions, RUNX3/SOCS1 promoter methylation, BRAF mutations, and microsatellite instability-high (MSI-H) status. By contrast, MLH1-unmethylated tumors were associated with earlier age of onset, increased distal colorectal localization, adverse pathologic features, and KRAS mutations. In the TCGA dataset, the MLH1-silenced CIMP-H CRC demonstrated proximal location, MSI-H status, hypermutated phenotype, and frequent BRAF mutations, but the MLH1-non-silenced CIMP-H CRC was significantly associated with high frequencies of KRAS and APC mutations. In conclusion, the differential nature of CIMP-H CRCs depends primarily on the MLH1 methylation status. Based on the current knowledge, the sessile serrated adenoma/polyp may be the major precursor of MLH1-methylated CIMP-H CRCs, whereas MLH1-unmethylated CIMP-H CRCs may develop predominantly from KRAS-mutated traditional serrated adenomas and less commonly from BRAF-mutated traditional serrated adenomas and/or sessile serrated adenomas/polyps.

Class A CpG Oligonucleotide Priming Rescues Mice from Septic Shock via Activation of Platelet-Activating Factor Acetylhydrolase

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Yoshinari Yamamoto

2017-08-01

Full Text Available Sepsis is a life-threatening, overwhelming immune response to infection with high morbidity and mortality. Inflammatory response and blood clotting are caused by sepsis, which induces serious organ damage and death from shock. As a mechanism of pathogenesis, platelet-activating factor (PAF induces excessive inflammatory responses and blood clotting. In this study, we demonstrate that a Class A CpG oligodeoxynucleotide (CpG-A1585 strongly induced PAF acetylhydrolase, which generates lyso-PAF. CpG-A1585 rescued mice from acute lethal shock and decreased fibrin deposition, a hallmark of PAF-induced disseminated intravascular coagulation. Furthermore, CpG-A1585 improved endotoxin shock induced by lipopolysaccharide, which comprises the cell wall of Gram-negative bacteria and inhibits inflammatory responses induced by cytokines such as interleukin-6 and tumor necrosis factor-α. These results suggest that CpG-A1585 is a potential therapeutic target to prevent sepsis-related induction of PAF.

Integrative DNA methylation and gene expression analysis to assess the universality of the CpG island methylator phenotype.

Science.gov (United States)

Moarii, Matahi; Reyal, Fabien; Vert, Jean-Philippe

2015-10-13

The CpG island methylator phenotype (CIMP) was first characterized in colorectal cancer but since has been extensively studied in several other tumor types such as breast, bladder, lung, and gastric. CIMP is of clinical importance as it has been reported to be associated with prognosis or response to treatment. However, the identification of a universal molecular basis to define CIMP across tumors has remained elusive. We perform a genome-wide methylation analysis of over 2000 tumor samples from 5 cancer sites to assess the existence of a CIMP with common molecular basis across cancers. We then show that the CIMP phenotype is associated with specific gene expression variations. However, we do not find a common genetic signature in all tissues associated with CIMP. Our results suggest the existence of a universal epigenetic and transcriptomic signature that defines the CIMP across several tumor types but does not indicate the existence of a common genetic signature of CIMP.

Excluding black hole firewalls with extreme cosmic censorship

Energy Technology Data Exchange (ETDEWEB)

Page, Don N., E-mail: profdonpage@gmail.com [Department of Physics, 4-183 CCIS, University of Alberta, Edmonton, Alberta T6G 2E1 (Canada)

2014-06-01

The AMPS argument for black hole firewalls seems to arise not only from the assumption of local effective field theory outside the stretched horizon but also from an overcounting of internal black hole states that include states that are singular in the past. Here I propose to exclude such singular states by Extreme Cosmic Censorship (the conjectured principle that the universe is entirely nonsingular, except for transient singularities inside black and/or white holes). I argue that the remaining set of nonsingular realistic states do not have firewalls but yet preserve information in Hawking radiation from black holes that form from nonsingular initial states.

Excluding black hole firewalls with extreme cosmic censorship

International Nuclear Information System (INIS)

Page, Don N.

2014-01-01

The AMPS argument for black hole firewalls seems to arise not only from the assumption of local effective field theory outside the stretched horizon but also from an overcounting of internal black hole states that include states that are singular in the past. Here I propose to exclude such singular states by Extreme Cosmic Censorship (the conjectured principle that the universe is entirely nonsingular, except for transient singularities inside black and/or white holes). I argue that the remaining set of nonsingular realistic states do not have firewalls but yet preserve information in Hawking radiation from black holes that form from nonsingular initial states

20 CFR 30.718 - How is a provider notified of OWCP's intent to exclude him or her?

Science.gov (United States)

2010-04-01

... 20 Employees' Benefits 1 2010-04-01 2010-04-01 false How is a provider notified of OWCP's intent to exclude him or her? 30.718 Section 30.718 Employees' Benefits OFFICE OF WORKERS' COMPENSATION... OWCP's intent to exclude him or her? The Regional Director shall initiate the exclusion process by...

Assessment of clusters of transcription factor binding sites in relationship to human promoter, CpG islands and gene expression

Directory of Open Access Journals (Sweden)

Sakaki Yoshiyuki

2004-02-01

Full Text Available Abstract Background Gene expression is regulated mainly by transcription factors (TFs that interact with regulatory cis-elements on DNA sequences. To identify functional regulatory elements, computer searching can predict TF binding sites (TFBS using position weight matrices (PWMs that represent positional base frequencies of collected experimentally determined TFBS. A disadvantage of this approach is the large output of results for genomic DNA. One strategy to identify genuine TFBS is to utilize local concentrations of predicted TFBS. It is unclear whether there is a general tendency for TFBS to cluster at promoter regions, although this is the case for certain TFBS. Also unclear is the identification of TFs that have TFBS concentrated in promoters and to what level this occurs. This study hopes to answer some of these questions. Results We developed the cluster score measure to evaluate the correlation between predicted TFBS clusters and promoter sequences for each PWM. Non-promoter sequences were used as a control. Using the cluster score, we identified a PWM group called PWM-PCP, in which TFBS clusters positively correlate with promoters, and another PWM group called PWM-NCP, in which TFBS clusters negatively correlate with promoters. The PWM-PCP group comprises 47% of the 199 vertebrate PWMs, while the PWM-NCP group occupied 11 percent. After reducing the effect of CpG islands (CGI against the clusters using partial correlation coefficients among three properties (promoter, CGI and predicted TFBS cluster, we identified two PWM groups including those strongly correlated with CGI and those not correlated with CGI. Conclusion Not all PWMs predict TFBS correlated with human promoter sequences. Two main PWM groups were identified: (1 those that show TFBS clustered in promoters associated with CGI, and (2 those that show TFBS clustered in promoters independent of CGI. Assessment of PWM matches will allow more positive interpretation of TFBS in

MicroRNA-31 expression in relation to BRAF mutation, CpG island methylation and colorectal continuum in serrated lesions.

Science.gov (United States)

Ito, Miki; Mitsuhashi, Kei; Igarashi, Hisayoshi; Nosho, Katsuhiko; Naito, Takafumi; Yoshii, Shinji; Takahashi, Hiroaki; Fujita, Masahiro; Sukawa, Yasutaka; Yamamoto, Eiichiro; Takahashi, Taiga; Adachi, Yasushi; Nojima, Masanori; Sasaki, Yasushi; Tokino, Takashi; Baba, Yoshifumi; Maruyama, Reo; Suzuki, Hiromu; Imai, Kohzoh; Yamamoto, Hiroyuki; Shinomura, Yasuhisa

2014-12-01

The CpG island methylator phenotype (CIMP) is a distinct form of epigenomic instability. Many CIMP-high colorectal cancers (CRCs) with BRAF mutation are considered to arise from serrated pathway. We recently reported that microRNA-31 (miR-31) is associated with BRAF mutation in colorectal tumors. Emerging new approaches have revealed gradual changes in BRAF mutation and CIMP-high throughout the colorectum in CRCs. Here, we attempted to identify a possible association between miR-31 and epigenetic features in serrated pathway, and hypothesized that miR-31 supports the "colorectal continuum" concept. We evaluated miR-31 expression, BRAF mutation and epigenetic features including CIMP status in 381 serrated lesions and 222 non-serrated adenomas and examined associations between them and tumor location (rectum; sigmoid, descending, transverse and ascending colon and cecum). A significant association was observed between high miR-31 expression and CIMP-high status in serrated lesions with BRAF mutation (p = 0.0001). In contrast, miR-31 was slightly but insignificantly associated with CIMP status in the cases with wild-type BRAF. miR-31 expression in sessile serrated adenomas (SSAs) with cytological dysplasia was higher than that in SSAs, whereas, no significant difference was observed between traditional serrated adenomas (TSAs) and TSAs with high-grade dysplasia. The frequency of miR-31, BRAF mutation CIMP-high and MLH1 methylation increased gradually from the rectum to cecum in serrated lesions. In conclusion, miR-31 expression was associated with CIMP-high status in serrated lesions with BRAF mutation. Our data also suggested that miR-31 plays an important role in SSA evolution and may be a molecule supporting the colorectal continuum. © 2014 UICC.

Bateman's Principle in Cooperatively Breeding Vertebrates: The Effects of Non-breeding Alloparents on Variability in Female and Male Reproductive Success.

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Hauber, Mark E; Lacey, Eileen A

2005-11-01

The sex-specific slopes of Bateman's gradients have important implications for understanding animal mating systems, including patterns of sexual selection and reproductive competition. Intersexual differences in the fitness benefits derived from mating with multiple partners are expected to yield distinct patterns of reproductive success for males and females, with variance in direct fitness predicted to be greater among males. These analyses assume that typically all adults are reproductive and that failure to produce offspring is non-adaptive. Among some species of cooperatively breeding birds and mammals, however, non-breeding adult alloparents are common and may comprise the majority of individuals in social groups. The presence of a large number of non-breeding adults, particularly when coupled with greater social suppression of reproduction among females, may alter the relative variance in direct fitness between the sexes, thereby generating an apparent contradiction to Bateman's Paradigm. To explore quantitatively the effects of non-breeding alloparents on variance in reproductive success, we used genetic estimates of parentage and reproductive success drawn from the literature to calculate the relative variability in direct fitness for females and males in alloparental and "other" societies of birds and mammals. Our analyses indicate that in mammals and, to a lesser extent, in birds, variability in direct fitness is greater among females in species characterized by the presence of non-breeding alloparents. These data suggest that social interactions, including social suppression of reproduction, are powerful determinants of individual direct fitness that may modify sex-specific patterns of reproductive variance from those described by Bateman.

CpG island methylator phenotype and prognosis of colorectal cancer in Northeast China.

Science.gov (United States)

Li, Xia; Hu, Fulan; Wang, Yibaina; Yao, Xiaoping; Zhang, Zuoming; Wang, Fan; Sun, Guizhi; Cui, Bin-Bin; Dong, Xinshu; Zhao, Yashuang

2014-01-01

To investigate the association between CpG island methylator phenotype (CIMP) and the overall survival of sporadic colorectal cancer (CRC) in Northeast China. 282 sporadic CRC patients were recruited in this study. We selected MLH1, MGMT, p16, APC, MINT1, MINT31, and RUNX3 as the CIMP panel markers. The promoter methylation was assessed by methylation sensitive high resolution melting (MS-HRM). Proportional hazards-regression models were fitted with computing hazard ratios (HR) and the corresponding 95% confidence intervals (95% CI). 12.77% (36/282) of patients were CIMP-0, 74.1% (209/282) of patients were CIMP-L, and 13.12% (37/282) of patients were CIMP-H. The five-year survival of the 282 CRC patients was 58%. There was significant association between APC gene promoter methylation and CRC overall survival (HR = 1.61; 95% CI: 1.05-2.46; P = 0.03). CIMP-H was significantly associated with worse prognosis compared to CIMP-0 (HR = 3.06; 95% CI: 1.19-7.89; P = 0.02) and CIMP-L (HR = 1.97; 95% CI: 1.11-3.48; P = 0.02), respectively. While comparing with the combine of CIMP-L and CIMP-0 (CIMP-L/0), CIMP-H also presented a worse prognosis (HR = 2.31; 95% CI: 1.02-5.24; P = 0.04). CIMP-H may be a predictor of a poor prognosis of CRC in Northeast China patients.

Recommendations for sustainable development of non-timber forest products

Science.gov (United States)

Gina H. Mohammed

2001-01-01

Non-timber forest products--or NTFPs--are considered here to be botanical products harvested or originating from forest-based species, but excluding primary timber products, industrial boards and composites, and paper products. A recent study of non-timber forest products in Ontario, Canada, identified at least 50 types of NTFPs and hundreds of specific products used...

B vitamins, methionine and alcohol intake and risk of colon cancer in relation to BRAF mutation and CpG island methylator phenotype (CIMP).

Science.gov (United States)

Schernhammer, Eva S; Giovannucci, Edward; Baba, Yoshifumi; Fuchs, Charles S; Ogino, Shuji

2011-01-01

One-carbon metabolism appears to play an important role in DNA methylation reaction. Evidence suggests that a low intake of B vitamins or high alcohol consumption increases colorectal cancer risk. How one-carbon nutrients affect the CpG island methylator phenotype (CIMP) or BRAF mutation status in colon cancer remains uncertain. Utilizing incident colon cancers in a large prospective cohort of women (the Nurses' Health Study), we determined BRAF status (N = 386) and CIMP status (N = 375) by 8 CIMP-specific markers [CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1], and 8 other CpG islands (CHFR, HIC1, IGFBP3, MGMT, MINT-1, MINT-31, p14, and WRN). We examined the relationship between intake of one-carbon nutrients and alcohol and colon cancer risk, by BRAF mutation or CIMP status. Higher folate intake was associated with a trend towards low risk of CIMP-low/0 tumors [total folate intake ≥400 µg/day vs. CIMP-high tumor risks (P(heterogeneity) = 0.73). Neither vitamin B(6), methionine or alcohol intake appeared to differentially influence risks for CIMP-high and CIMP-low/0 tumors. Using the 16-marker CIMP panel did not substantially alter our results. B vitamins, methionine or alcohol intake did not affect colon cancer risk differentially by BRAF status. This molecular pathological epidemiology study suggests that low level intake of folate may be associated with an increased risk of CIMP-low/0 colon tumors, but not that of CIMP-high tumors. However, the difference between CIMP-high and CIMP-low/0 cancer risks was not statistically significant, and additional studies are necessary to confirm these observations.

Genetic polymorphisms in one-carbon metabolism: associations with CpG island methylator phenotype (CIMP) in colon cancer and the modifying effects of diet.

Science.gov (United States)

Curtin, Karen; Slattery, Martha L; Ulrich, Cornelia M; Bigler, Jeannette; Levin, Theodore R; Wolff, Roger K; Albertsen, Hans; Potter, John D; Samowitz, Wade S

2007-08-01

This study investigated associations between CpG island methylator phenotype (CIMP) colon cancer and genetic polymorphisms relevant to one-carbon metabolism and thus, potentially the provision of methyl groups and risk of colon cancer. Data from a large, population-based case-control study (916 incident colon cancer cases and 1,972 matched controls) were used. Candidate polymorphisms in methylenetetrahydrofolate reductase (MTHFR), thymidylate synthase (TS), transcobalamin II (TCNII), methionine synthase (MTR), reduced folate carrier (RFC), methylenetetrahydrofolate dehydrogenase 1 (MTHFD1), dihydrofolate reductase (DHFR) and alcohol dehydrogenase 3 (ADH3) were evaluated. CIMP- or CIMP+ phenotype was based on five CpG island markers: MINT1, MINT2, MINT31, p16 and MLH1. The influence of specific dietary factors (folate, methionine, vitamin B(12) and alcohol) on these associations was also analyzed. We hypothesized that polymorphisms involved in the provision of methyl groups would be associated with CIMP+ tumors (two or more of five markers methylated), potentially modified by diet. Few associations specific to CIMP+ tumors were observed overall, which does not support the hypothesis that the provision of methyl groups is important in defining a methylator phenotype. However, our data suggest that genetic polymorphisms in MTHFR 1,298A > C, interacting with diet, may be involved in the development of highly CpG-methylated colon cancers. AC and CC genotypes in conjunction with a high-risk dietary pattern (low folate and methionine intake and high alcohol use) were associated with CIMP+ (OR = 2.1, 95% CI = 1.3-3.4 versus AA/high risk; P-interaction = 0.03). These results provide only limited support for a role of polymorphisms in one-carbon metabolism in the etiology of CIMP colon cancer.

20 CFR 10.818 - How is a provider notified of OWCP's intent to exclude him or her?

Science.gov (United States)

2010-04-01

... 20 Employees' Benefits 1 2010-04-01 2010-04-01 false How is a provider notified of OWCP's intent to exclude him or her? 10.818 Section 10.818 Employees' Benefits OFFICE OF WORKERS' COMPENSATION... How is a provider notified of OWCP's intent to exclude him or her? The Regional Director shall...

Breast MRI used as a problem-solving tool reliably excludes malignancy

International Nuclear Information System (INIS)

Spick, Claudio; Szolar, Dieter H.M.; Preidler, Klaus W.; Tillich, Manfred; Reittner, Pia; Baltzer, Pascal A.

2015-01-01

Highlights: • Breast MRI reliably excludes malignancy in conventional BI-RADS 0 cases (NPV: 100%). • Malignancy rate in the BI-RADS 0 population is substantial with 13.5%. • Breast MRI used as a problem-solving tool reliably excludes malignancy. - Abstract: Purpose: To evaluate the diagnostic performance of breast MRI if used as a problem-solving tool in BI-RADS 0 cases. Material and methods: In this IRB-approved, single-center study, 687 women underwent high-resolution-3D, dynamic contrast-enhanced breast magnetic resonance imaging (MRI) between January 2012 and December 2012. Of these, we analyzed 111 consecutive patients (mean age, 51 ± 12 years; range, 20–83 years) categorized as BI-RADS 0. Breast MRI findings were stratified by clinical presentations, conventional imaging findings, and breast density. MRI results were compared to the reference standard, defined as histopathology or an imaging follow-up of at least 1 year. Results: One hundred eleven patients with BI-RADS 0 conventional imaging findings revealed 30 (27%) mammographic masses, 57 (51.4%) mammographic architectural distortions, five (4.5%) mammographic microcalcifications, 17 (15.3%) ultrasound-only findings, and two palpable findings without imaging correlates. There were 15 true-positive, 85 true-negative, 11 false-positive, and zero false-negative breast MRI findings, resulting in a sensitivity, specificity, PPV, and NPV of 100% (15/15), 88.5% (85/96), 57.7% (15/26), and 100% (85/85), respectively. Breast density and reasons for referral had no significant influence on the diagnostic performance of breast MRI (p > 0.05). Conclusion: Breast MRI reliably excludes malignancy in conventional BI-RADS 0 cases resulting in a NPV of 100% (85/85) and a PPV of 57.7% (15/26)

Excluded from School: Getting a Second Chance at a "Meaningful" Education

Science.gov (United States)

McGregor, Glenda; Mills, Martin; te Riele, Kitty; Hayes, Debra

2015-01-01

In this paper, we draw upon the experiences of a group of young people who have been excluded from mainstream schools in two Australian states to provide an account of the ways in which they have found their way to education in educational sites that are variously referred to as "flexible learning centres", "second chance…

Variable Omission of "ne" in Real-Time French Chat: A Corpus-Driven Comparison of Educational and Non-Educational Contexts

Science.gov (United States)

van Compernolle, Remi A.; Williams, Lawrence

2009-01-01

This article reports on the variable omission of the French negative particle "ne" (the first marker of verbal negation) in synchronous (i.e., real-time) electronic communication environments. Patterns of variation in a corpus of non-educational chat (i.e., free, public-access Internet chat) are analyzed and compared to data produced by first-,…

DNA methylation at a bovine alpha satellite I repeat CpG site during development following fertilization and somatic cell nuclear transfer.

Directory of Open Access Journals (Sweden)

Christine Couldrey

Full Text Available Incomplete epigenetic reprogramming is postulated to contribute to the low developmental success following somatic cell nuclear transfer (SCNT. Here, we describe the epigenetic reprogramming of DNA methylation at an alpha satellite I CpG site (αsatI-5 during development of cattle generated either by artificial insemination (AI or in vitro fertilization (IVF and SCNT. Quantitative methylation analysis identified that SCNT donor cells were highly methylated at αsatI-5 and resulting SCNT blastocysts showed significantly more methylation than IVF blastocysts. At implantation, no difference in methylation was observed between SCNT and AI in trophoblast tissue at αsatI-5, however, SCNT embryos were significantly hyper-methylated compared to AI controls at this time point. Following implantation, DNA methylation at αsatI-5 decreased in AI but not SCNT placental tissues. In contrast to placenta, the proportion of methylation at αsatI-5 remained high in adrenal, kidney and muscle tissues during development. Differences in the average proportion of methylation were smaller in somatic tissues than placental tissues but, on average, SCNT somatic tissues were hyper-methylated at αsatI-5. Although sperm from all bulls was less methylated than somatic tissues at αsatI-5, on average this site remained hyper-methylated in sperm from cloned bulls compared with control bulls. This developmental time course confirms that epigenetic reprogramming does occur, at least to some extent, following SCNT. However, the elevated methylation levels observed in SCNT blastocysts and cellular derivatives implies that there is either insufficient time or abundance of appropriate reprogramming factors in oocytes to ensure complete reprogramming. Incomplete reprogramming at this CpG site may be a contributing factor to low SCNT success rates, but more likely represents the tip of the iceberg in terms of incompletely reprogramming. Until protocols ensure the epigenetic

Board Size, Non-Executive Board Members and Financial Performance in Non-Usury Banks in Iran

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GholamReza Karami

2016-07-01

Full Text Available Prior studies investigating the relation between the financial performance and corporate governance mechanisms for firms in Tehran Stock Exchange mainly exclude banks due to their different types of rules and structure. We study the relation between corporate governance structure and financial performance of the banks under the non-usury banking act. We study various corporate governance factors including board size and the number of non-executive board members using a sample of 21 banks for 2010 to 2012. Result show a significant positive correlation among board size and financial performance. However, non-executive board members do not correlate with financial performance.

POVMs and hidden variables

International Nuclear Information System (INIS)

Stairs, Allen

2007-01-01

Recent results by Paul Busch and Adan Cabello claim to show that by appealing to POVMs, non-contextual hidden variables can be ruled out in two dimensions. While the results of Busch and Cabello are mathematically correct, interpretive problems render them problematic as no hidden variable proofs

An Arithmetical Hierarchy of the Law of Excluded Middle and Related Principles

DEFF Research Database (Denmark)

Akama, Yohji; Berardi, Stefano; Hayashi, Susumu

2004-01-01

's Lemma, Post's Theorem, Excluded Middle for simply Existential and simply Universal statements, and many others.Our motivations are rooted in the experience of one of the authors with an extended program extraction and of another author with bound extraction from classical proofs....

40 CFR Table 4 to Subpart Jj of... - Pollutants Excluded From Use in Cleaning and Washoff Solvents

Science.gov (United States)

2010-07-01

... 40 Protection of Environment 10 2010-07-01 2010-07-01 false Pollutants Excluded From Use in Cleaning and Washoff Solvents 4 Table 4 to Subpart JJ of Part 63 Protection of Environment ENVIRONMENTAL... Operations Pt. 63, Subpt. JJ, Table 4 Table 4 to Subpart JJ of Part 63—Pollutants Excluded From Use in...

A downstream CpG island controls transcript initiation and elongation and the methylation state of the imprinted Airn macro ncRNA promoter.

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Martha V Koerner

Full Text Available A CpG island (CGI lies at the 5' end of the Airn macro non-protein-coding (nc RNA that represses the flanking Igf2r promoter in cis on paternally inherited chromosomes. In addition to being modified on maternally inherited chromosomes by a DNA methylation imprint, the Airn CGI shows two unusual organization features: its position immediately downstream of the Airn promoter and transcription start site and a series of tandem direct repeats (TDRs occupying its second half. The physical separation of the Airn promoter from the CGI provides a model to investigate if the CGI plays distinct transcriptional and epigenetic roles. We used homologous recombination to generate embryonic stem cells carrying deletions at the endogenous locus of the entire CGI or just the TDRs. The deleted Airn alleles were analyzed by using an ES cell imprinting model that recapitulates the onset of Igf2r imprinted expression in embryonic development or by using knock-out mice. The results show that the CGI is required for efficient Airn initiation and to maintain the unmethylated state of the Airn promoter, which are both necessary for Igf2r repression on the paternal chromosome. The TDRs occupying the second half of the CGI play a minor role in Airn transcriptional elongation or processivity, but are essential for methylation on the maternal Airn promoter that is necessary for Igf2r to be expressed from this chromosome. Together the data indicate the existence of a class of regulatory CGIs in the mammalian genome that act downstream of the promoter and transcription start.

Analisis Faktor Permintaan Non Fungsional Kelompok Non-Member Terhadap Permintaan (Seri 2

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Iskandar Putong

2011-11-01

Full Text Available Factor analysis of non functional Demand Non-Member On to Demand aimed to discover whether there is significant influence of non-functional variable on demand. Three independent variables (the effect, ie, X1 for Snob Effect (Mode, X2 for the Bandwagon effect (Prestige and X3 for the Veblen Effect (Show-off and 1 dependent variable Y for Demand. The number of respondents of 50 and 22 indicators is statistically valid. Analysis tool using the Model Correlation and simple Regression (Simple/Bivariate, Correlation and Regression Simultaneously (Multiple Regression and Partial Correlation. The results of analysis proved statistically with LOC of 95%, indicating that the bivariate, partial unison and Simultaneously there is positive and significant correlation between variables X to Y, except for variable X2 (Prestige on Bivariate correlation. 

The use of clinical practice guidelines in primary care: professional mindlines and control mechanisms.

Science.gov (United States)

Gené-Badia, Joan; Gallo, Pedro; Caïs, Jordi; Sánchez, Emília; Carrion, Carme; Arroyo, Liliana; Aymerich, Marta

2016-01-01

To identify the relevant barriers and enablers perceived by primary care professionals in implementing the recommendations of clinical practice guidelines (CPG). Two focus groups were conducted with primary care physicians and nurses in Catalonia (Spain) between October and December 2012. Thirty-nine health professionals were selected based on their knowledge and daily use of CPG. Finally, eight general practitioners and eight nurses were included in the discussion groups. Participants were asked to share their views and beliefs on the accessibility of CPG, their knowledge and use of these documents, the content and format of CPG, dissemination strategy, training, professional-patient relationship, and the use of CPG by the management structure. We recorded and transcribed the content verbatim and analysed the data using qualitative analysis techniques. Physicians believed that, overall, CPG were of little practical use and frequently referred to them as a largely bureaucratic management control instrument that threatened their professional autonomy. In contrast, nurses believed that CPG were rather helpful tools in their day-to-day practice, although they would like them to be more sensitive to the current role of nurses. Both groups believed that CPG did not provide a response to most of the decisions they faced in the primary care setting. Compliance with CPG recommendations would be improved if these documents were brief, non-compulsory, not cost-containment oriented, more based on nursing care models, sensitive to the specific needs of primary care patients, and integrated into the computer workstation. Copyright © 2016 SESPAS. Publicado por Elsevier España, S.L.U. All rights reserved.

Equitable access to health insurance for socially excluded children? The case of the National Health Insurance Scheme (NHIS) in Ghana.

Science.gov (United States)

Williams, Gemma A; Parmar, Divya; Dkhimi, Fahdi; Asante, Felix; Arhinful, Daniel; Mladovsky, Philipa

2017-08-01

To help reduce child mortality and reach universal health coverage, Ghana extended free membership of the National Health Insurance Scheme (NHIS) to children (under-18s) in 2008. However, despite the introduction of premium waivers, a substantial proportion of children remain uninsured. Thus far, few studies have explored why enrolment of children in NHIS may remain low, despite the absence of significant financial barriers to membership. In this paper we therefore look beyond economic explanations of access to health insurance to explore additional wider determinants of enrolment in the NHIS. In particular, we investigate whether social exclusion, as measured through a sociocultural, political and economic lens, can explain poor enrolment rates of children. Data were collected from a cross-sectional survey of 4050 representative households conducted in Ghana in 2012. Household indices were created to measure sociocultural, political and economic exclusion, and logistic regressions were conducted to study determinants of enrolment at the individual and household levels. Our results indicate that socioculturally, economically and politically excluded children are less likely to enrol in the NHIS. Furthermore, households excluded in all dimensions were more likely to be non-enrolled or partially-enrolled (i.e. not all children enrolled within the household) than fully-enrolled. These results suggest that equity in access for socially excluded children has not yet been achieved. Efforts should be taken to improve coverage by removing the remaining small, annually renewable registration fee, implementing and publicising the new clause that de-links premium waivers from parental membership, establishing additional scheme administrative offices in remote areas, holding regular registration sessions in schools and conducting outreach sessions and providing registration support to female guardians of children. Ensuring equitable access to NHIS will contribute substantially

Meta-analysis of the prognostic value of CpG island methylator phenotype in gastric cancer.

Science.gov (United States)

Powell, A G M T; Soul, S; Christian, A; Lewis, W G

2018-01-01

CpG island methylator phenotype (CIMP) has been identified as a distinct molecular subtype of gastric cancer, yet associations with survival are conflicting. A meta-analysis was performed to estimate the prognostic significance of CIMP. Embase, MEDLINE, PubMed, PubMed Central and Cochrane databases were searched systematically for studies related to the association between CIMP and survival in patients undergoing potentially curative resection for gastric cancer. A total of 918 patients from ten studies were included, and the median proportion of tumours with CIMP-high (CIMP-H) status was 40·9 (range 4·8-63) per cent. Gene panels for assessing CIMP status varied between the studies. Pooled analysis suggested that specimens exhibiting CIMP-H were associated with poorer 5-year survival (odds ratio (OR) for death 1·48, 95 per cent c.i. 1·10 to 1·99; P = 0·009). Significant heterogeneity was observed between studies (I 2 = 88 per cent, P CIMP-H tumours, revealed that CIMP-H was associated with both poor (OR for death 8·15, 4·65 to 14·28, P CIMP, which may explain the survival differences. © 2018 BJS Society Ltd Published by John Wiley & Sons Ltd.

Variable selection in Logistic regression model with genetic algorithm.

Science.gov (United States)

Zhang, Zhongheng; Trevino, Victor; Hoseini, Sayed Shahabuddin; Belciug, Smaranda; Boopathi, Arumugam Manivanna; Zhang, Ping; Gorunescu, Florin; Subha, Velappan; Dai, Songshi

2018-02-01

Variable or feature selection is one of the most important steps in model specification. Especially in the case of medical-decision making, the direct use of a medical database, without a previous analysis and preprocessing step, is often counterproductive. In this way, the variable selection represents the method of choosing the most relevant attributes from the database in order to build a robust learning models and, thus, to improve the performance of the models used in the decision process. In biomedical research, the purpose of variable selection is to select clinically important and statistically significant variables, while excluding unrelated or noise variables. A variety of methods exist for variable selection, but none of them is without limitations. For example, the stepwise approach, which is highly used, adds the best variable in each cycle generally producing an acceptable set of variables. Nevertheless, it is limited by the fact that it commonly trapped in local optima. The best subset approach can systematically search the entire covariate pattern space, but the solution pool can be extremely large with tens to hundreds of variables, which is the case in nowadays clinical data. Genetic algorithms (GA) are heuristic optimization approaches and can be used for variable selection in multivariable regression models. This tutorial paper aims to provide a step-by-step approach to the use of GA in variable selection. The R code provided in the text can be extended and adapted to other data analysis needs.

Increased variability of tornado occurrence in the United States.

Science.gov (United States)

Brooks, Harold E; Carbin, Gregory W; Marsh, Patrick T

2014-10-17

Whether or not climate change has had an impact on the occurrence of tornadoes in the United States has become a question of high public and scientific interest, but changes in how tornadoes are reported have made it difficult to answer it convincingly. We show that, excluding the weakest tornadoes, the mean annual number of tornadoes has remained relatively constant, but their variability of occurrence has increased since the 1970s. This is due to a decrease in the number of days per year with tornadoes combined with an increase in days with many tornadoes, leading to greater variability on annual and monthly time scales and changes in the timing of the start of the tornado season. Copyright © 2014, American Association for the Advancement of Science.

29 CFR 794.110 - Activities excluded from the enterprise by the statute.

Science.gov (United States)

2010-07-01

... definition quoted in § 794.106. The definition distinguishes between the related activities performed through... fide independent contractor (for example, an independent accounting or auditing firm). The latter activities are expressly excluded from the “enterprise” as defined. In addition, the definition contains a...

TSH alone is not sufficient to exclude all patients with a functioning thyroid nodule from undergoing testing to exclude thyroid cancer

Energy Technology Data Exchange (ETDEWEB)

Hurtado-Lopez, Luis-Mauricio; Monroy-Lozano, Blanca-Estela [General Hospital of Mexico, Mexico City (Mexico); Martinez-Duncker, Carlos [Hospital Infantil de Mexico Federico Gomez, Medicina Nuclear Molecular, Mexico City, DF (Mexico)

2008-06-15

The purpose of the study was to analyze whether the thyroid-stimulating hormone (TSH) alone avoids tests to exclude malignancy in all patients with functional thyroid nodules (FTN). Sixty-nine patients with FTN on {sup 99m}Tc scintigraphy, radioiodine uptake test (RIU), {sup 99m}Tc thyroid uptake, TSH assay, T3, and T4 obtained within 48 h were retrospectively identified out of 2,356 thyroid scans performed from January 2000 to April 2007. FTNs were classified as causing total, partial, or no inhibition of the thyroid as group 1, 2, or 3, respectively. TSH was subnormal in 21 of 69 (30.43%) patients. In group 1 (N = 23, 33.3%), TSH was subnormal, normal, and high in eight, nine, and six patients; in group 2 (N = 17, 24.6%), TSH was subnormal, normal, and high in four, six, and seven patients, and in group 3 (N = 29, 42%), TSH was subnormal, normal, and high in 9, 13, and 7 patients, respectively. TSH was significantly lower in group 1. In T3, T4, {sup 99m}Tc thyroid uptake, and RIU, there were no differences between the three groups. Only 30.43% of patients had subnormal TSH. TSH alone cannot avoid tests to exclude malignancy in all patients with FTN. FTN existence can only be accurately assessed by thyroid scintigraphy. The current incidence of FTN may be unknown because scintigraphy is not routinely performed in all patients with thyroid nodules. Thyroid scintigraphy of patients with high TSH can detect diseases such as Hashimoto's thyroiditis and identify patients with FTN in whom no further diagnostic procedures would be needed in patients with normal TSH levels with nondiagnostic fine-needle aspiration results. (orig.)

Oxytocin biases men but not women to restore social connections with individuals who socially exclude them

OpenAIRE

Xu, Xiaolei; Yao, Shuxia; Xu, Lei; Geng, Yayuan; Zhao, Weihua; Ma, Xiaole; Kou, Juan; Luo, Ruixue; Kendrick, Keith M.

2017-01-01

We normally react to individuals who exclude us socially by either avoiding them or increasing our attempts to interact with them. The neuropeptide oxytocin can promote social bonds and reduce social conflict and we therefore investigated whether it facilitates more positive social responses towards individuals who exclude or include us. In a double-blind, placebo-controlled, between-subject design 77 healthy Chinese male and female participants received intranasal oxytocin (40 IU) or placebo...

Variable Thermal Conductivity on Compressible Boundary Layer ...

African Journals Online (AJOL)

In this paper, variable thermal conductivity on heat transfer over a circular cylinder is presented. The concept of assuming constant thermal conductivity on materials is however not efficient. Hence, the governing partial differential equation is reduced using non-dimensionless variables into a system of coupled non-linear ...

Range and variability in gesture-based interactions with medical images : do non-stereo versus stereo visualizations elicit different types of gestures?

NARCIS (Netherlands)

Beurden, van M.H.P.H.; IJsselsteijn, W.A.

2010-01-01

The current paper presents a study into the range and variability of natural gestures when interacting with medical images, using traditional non stereo and stereoscopic modes of presentation. The results have implications for the design of computer-vision algorithms developed to support natural

9 CFR 130.19 - User fees for other veterinary diagnostic services or materials provided at NVSL (excluding FADDL).

Science.gov (United States)

2010-01-01

... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false User fees for other veterinary... User fees for other veterinary diagnostic services or materials provided at NVSL (excluding FADDL). (a) User fees for other veterinary diagnostic services or materials available from NVSL (excluding FADDL...

Hypermethylation of the 5′ CpG island of the p14ARF flanking exon 1β in human colorectal cancer displaying a restricted pattern of p53 overexpression concomitant with increased MDM2 expression

Directory of Open Access Journals (Sweden)

Nyiraneza Christine

2012-06-01

Full Text Available Abstract Background It has been suggested that inactivation of p14ARF, a tumor suppressor central to regulating p53 protein stability through interaction with the MDM2 oncoprotein, abrogates p53 activity in human tumors retaining the wild-type TP53 gene. Differences in expression of tumor suppressor genes are frequently associated with cancer. We previously reported on a pattern of restricted p53 immunohistochemical overexpression significantly associated with microsatellite instability (MSI, low TP53 mutation frequency, and MDM2 overexpression in colorectal cancers (CRCs. In this study, we investigated whether p14ARF alterations could be a mechanism for disabling the p53 pathway in this subgroup of CRCs. Results Detailed maps of the alterations in the p14ARF gene were determined in a cohort of 98 CRCs to detect both nucleotide and copy-number changes. Methylation-specific PCR combined with bisulfite sequencing was used to evaluate the prevalence and distribution of p14ARF methylation. p14ARF alterations were then correlated with MSI status, TP53 mutations, and immunohistochemical expression of p53 and MDM2. The frequency of p14ARF mutations was extremely low (1/98; 1%, whereas coexistence of methylated and unmethylated alleles in both tumors and normal colon mucosa was common (91/98; 93%. Only seven of ninety-eight tumors (7% had a distinct pattern of methylation compared with normal colon mucosa. Evaluation of the prevalence and distribution of p14ARF promoter methylation in a region containing 27 CpG sites in 35 patients showed a range of methylated CpG sites in tumors (0 to 25 (95% CI 1 to 13 versus 0 to 17 (95% CI 0 to 2 in adjacent colon mucosa (P = 0.004. Hypermethylation of the p14ARF promoter was significantly correlated with the restricted p53 overexpression pattern (P = 0.03, and MDM2 overexpression (P = 0.02, independently of MSI phenotype. Although no significant correlation between p14ARF methylation and TP53 mutational

An innovative statistical approach for analysing non-continuous variables in environmental monitoring: assessing temporal trends of TBT pollution.

Science.gov (United States)

Santos, José António; Galante-Oliveira, Susana; Barroso, Carlos

2011-03-01

The current work presents an innovative statistical approach to model ordinal variables in environmental monitoring studies. An ordinal variable has values that can only be compared as "less", "equal" or "greater" and it is not possible to have information about the size of the difference between two particular values. The example of ordinal variable under this study is the vas deferens sequence (VDS) used in imposex (superimposition of male sexual characters onto prosobranch females) field assessment programmes for monitoring tributyltin (TBT) pollution. The statistical methodology presented here is the ordered logit regression model. It assumes that the VDS is an ordinal variable whose values match up a process of imposex development that can be considered continuous in both biological and statistical senses and can be described by a latent non-observable continuous variable. This model was applied to the case study of Nucella lapillus imposex monitoring surveys conducted in the Portuguese coast between 2003 and 2008 to evaluate the temporal evolution of TBT pollution in this country. In order to produce more reliable conclusions, the proposed model includes covariates that may influence the imposex response besides TBT (e.g. the shell size). The model also provides an analysis of the environmental risk associated to TBT pollution by estimating the probability of the occurrence of females with VDS ≥ 2 in each year, according to OSPAR criteria. We consider that the proposed application of this statistical methodology has a great potential in environmental monitoring whenever there is the need to model variables that can only be assessed through an ordinal scale of values.

Characterizing the strand-specific distribution of non-CpG methylation in human pluripotent cells.

Science.gov (United States)

Guo, Weilong; Chung, Wen-Yu; Qian, Minping; Pellegrini, Matteo; Zhang, Michael Q

2014-03-01

DNA methylation is an important defense and regulatory mechanism. In mammals, most DNA methylation occurs at CpG sites, and asymmetric non-CpG methylation has only been detected at appreciable levels in a few cell types. We are the first to systematically study the strand-specific distribution of non-CpG methylation. With the divide-and-compare strategy, we show that CHG and CHH methylation are not intrinsically different in human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). We also find that non-CpG methylation is skewed between the two strands in introns, especially at intron boundaries and in highly expressed genes. Controlling for the proximal sequences of non-CpG sites, we show that the skew of non-CpG methylation in introns is mainly guided by sequence skew. By studying subgroups of transposable elements, we also found that non-CpG methylation is distributed in a strand-specific manner in both short interspersed nuclear elements (SINE) and long interspersed nuclear elements (LINE), but not in long terminal repeats (LTR). Finally, we show that on the antisense strand of Alus, a non-CpG site just downstream of the A-box is highly methylated. Together, the divide-and-compare strategy leads us to identify regions with strand-specific distributions of non-CpG methylation in humans.

Strong Decomposition of Random Variables

DEFF Research Database (Denmark)

Hoffmann-Jørgensen, Jørgen; Kagan, Abram M.; Pitt, Loren D.

2007-01-01

A random variable X is stongly decomposable if X=Y+Z where Y=Φ(X) and Z=X-Φ(X) are independent non-degenerated random variables (called the components). It is shown that at least one of the components is singular, and we derive a necessary and sufficient condition for strong decomposability...... of a discrete random variable....

Magnetic charge and non-associative algebras

International Nuclear Information System (INIS)

Guenaydin, M.; Zumino, B.

1985-02-01

We consider the possibility that the quantum mechanics of a nonrelativistic electron in the magnetic field of a magnetic charge distribution can be described in terms of a non-associative algebra of observables. It appears that the case of a point monopole is excluded, while that of a constant charge distribution is acceptable. 21 references

31 CFR 19.430 - How do I check to see if a person is excluded or disqualified?

Science.gov (United States)

2010-07-01

... 31 Money and Finance: Treasury 1 2010-07-01 2010-07-01 false How do I check to see if a person is excluded or disqualified? 19.430 Section 19.430 Money and Finance: Treasury Office of the Secretary of the... disqualified? You check to see if a person is excluded or disqualified in two ways: (a) You as an agency...

Liver stiffness plus platelet count can be used to exclude high-risk oesophageal varices.

Science.gov (United States)

Ding, Nik S; Nguyen, Tin; Iser, David M; Hong, Thai; Flanagan, Emma; Wong, Avelyn; Luiz, Lauren; Tan, Jonathan Y C; Fulforth, James; Holmes, Jacinta; Ryan, Marno; Bell, Sally J; Desmond, Paul V; Roberts, Stuart K; Lubel, John; Kemp, William; Thompson, Alexander J

2016-02-01

Endoscopic screening for high-risk gastro-oesophageal varices (GOV) is recommended for compensated cirrhotic patients with transient elastography identifying increasing numbers of patients with cirrhosis without portal hypertension. Using liver stiffness measurement (LSM) ± platelet count, the aim was to develop a simple clinical rule to exclude the presence of high-risk GOV in patients with Child-Pugh A cirrhosis. A retrospective analysis of 71 patients with Child-Pugh A cirrhosis diagnosed by transient elastography (LSM >13.6 kPa) who underwent screening gastroscopy was conducted. A predictive model using LSM ± platelet count was assessed to exclude the presence of high-risk GOV (diameter >5 mm and/or the presence of high-risk stigmata) and validated using a second cohort of 200 patients from two independent centres. High-risk GOV were present in 10 (15%) and 16 (8%) of the training and validation cohorts, respectively, which was associated with LSM and Pl count (P < 0.05). A combined model based on LSM and Pl count was more accurate for excluding the presence of high-risk GOV than either alone (training cohort AUROC: 0.87 [0.77-0.96] vs. 0.78 [0.65-0.92] for LSM and 0.71 [0.52-0.90] for platelets) with the combination of LSM ≤25 kPa and Pl ≥100 having a NPV of 100% in both the training and validation cohorts. A total of 107 (39%) patients meet this criterion. The combination of LSM ≤25 kPa and Pl ≥100 can be used in clinical practice to exclude the presence of high-risk GOV in patients with Child-Pugh A cirrhosis. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

9 CFR 130.16 - User fees for veterinary diagnostic serology tests performed at NVSL (excluding FADDL) or at...

Science.gov (United States)

2010-01-01

... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false User fees for veterinary diagnostic serology tests performed at NVSL (excluding FADDL) or at authorized sites. 130.16 Section 130.16 Animals... USER FEES § 130.16 User fees for veterinary diagnostic serology tests performed at NVSL (excluding...

Embolization for non-variceal upper gastrointestinal tract haemorrhage: A systematic review

Energy Technology Data Exchange (ETDEWEB)

Mirsadraee, S.; Tirukonda, P.; Nicholson, A. [Department of Radiology, Leeds General Infirmary, Leeds (United Kingdom); Everett, S.M. [Department of Gastroenterology, Leeds General Infirmary, Leeds (United Kingdom); McPherson, S.J., E-mail: simon.mcpherson@leedsth.nhs.u [Department of Radiology, Leeds General Infirmary, Leeds (United Kingdom)

2011-06-15

Aim: To assess the published evidence on the endovascular treatment of non-variceal upper gastrointestinal haemorrhage. Materials and methods: An Ovid Medline search of published literature was performed (1966-2009). Non-English literature, experimental studies, variceal haemorrhage and case series with fewer than five patients were excluded. The search yielded 1888 abstracts. Thirty-five articles were selected for final analysis. Results: The total number of pooled patients was 927. The technical and clinical success of embolization ranged from 52-100% and 44-100%, respectively. The pooled mean technical/clinical success rate in primary upper gastrointestinal tract haemorrhage (PUGITH) only, trans-papillary haemorrhage (TPH) only, and mixed studies were 84%/67%, 93%/89%, and 93%/64%, respectively. Clinical outcome was adversely affected by multi-organ failure, shock, corticosteroids, transfusion, and coagulopathy. The anatomical source of haemorrhage and procedural variables did not affect the outcome. A successful embolization improved survival by 13.3 times. Retrospective comparison with surgery demonstrated equivalent mortality and clinical success, despite embolization being applied to a more elderly population with a higher prevalence of co-morbidities. Conclusions: Embolization is effective in this very difficult cohort of patients with outcomes similar to surgery.

The Relationship Between Cognitive and Non-Cognitive Variables and Academic Performance of Students in the Science Enrichment Preparation (S.E.P.) Program

Science.gov (United States)

Borden, Paula D.

This dissertation study concerned the lack of underrepresented minority students matriculating through the health professions pipeline. The term pipeline is "the educational avenue by which one must travel to successfully enter a profession" (Sullivan Alliance, 2004). There are a significant number of health professional pipeline programs based across the United States and, for the purposes of this study, a focus was placed on the Science Enrichment Preparation (S.E.P.) Program which is based at The University of North Carolina at Chapel Hill. The S.E.P. Program, is an eight-week residential summer experience, designed to support underrepresented minority pre-health students develop the competitive edge for successful admission into health professional school programs. The bedrock of this dissertation study concerned itself with the relationships between cognitive variables and non-cognitive variables and academic performance of students in the S.E.P. Program from 2005-2013. The study was undertaken to provide a clearer understanding for the NC Health Careers Access Program's (NC-HCAP) leadership with regard to variables associated with the students' academic performance in the S.E.P. Program. The data outcomes were informative for NC-HCAP in identifying cognitive and non-cognitive variables associated with student academic performance. Additionally, these findings provided direction as to what infrastructures may be put into place to more effectively support the S.E.P. participants. It is the researcher's hope this study may serve as an educational model and resource to pipeline programs and others with similar educational missions. The consequences and implications of a non-diverse healthcare workforce are high and far reaching. Without parity representation in the healthcare workforce, health disparities between racial and economic groups will likely continue to grow.

pEPito: a significantly improved non-viral episomal expression vector for mammalian cells

Directory of Open Access Journals (Sweden)

Ogris Manfred

2010-03-01

Full Text Available Abstract Background The episomal replication of the prototype vector pEPI-1 depends on a transcription unit starting from the constitutively expressed Cytomegalovirus immediate early promoter (CMV-IEP and directed into a 2000 bp long matrix attachment region sequence (MARS derived from the human β-interferon gene. The original pEPI-1 vector contains two mammalian transcription units and a total of 305 CpG islands, which are located predominantly within the vector elements necessary for bacterial propagation and known to be counterproductive for persistent long-term transgene expression. Results Here, we report the development of a novel vector pEPito, which is derived from the pEPI-1 plasmid replicon but has considerably improved efficacy both in vitro and in vivo. The pEPito vector is significantly reduced in size, contains only one transcription unit and 60% less CpG motives in comparison to pEPI-1. It exhibits major advantages compared to the original pEPI-1 plasmid, including higher transgene expression levels and increased colony-forming efficiencies in vitro, as well as more persistent transgene expression profiles in vivo. The performance of pEPito-based vectors was further improved by replacing the CMV-IEP with the human CMV enhancer/human elongation factor 1 alpha promoter (hCMV/EF1P element that is known to be less affected by epigenetic silencing events. Conclusions The novel vector pEPito can be considered suitable as an improved vector for biotechnological applications in vitro and for non-viral gene delivery in vivo.

CpG Island Methylator Phenotype and Prognosis of Colorectal Cancer in Northeast China

Directory of Open Access Journals (Sweden)

Xia Li

2014-01-01

Full Text Available Purpose. To investigate the association between CpG island methylator phenotype (CIMP and the overall survival of sporadic colorectal cancer (CRC in Northeast China. Methods. 282 sporadic CRC patients were recruited in this study. We selected MLH1, MGMT, p16, APC, MINT1, MINT31, and RUNX3 as the CIMP panel markers. The promoter methylation was assessed by methylation sensitive high resolution melting (MS-HRM. Proportional hazards-regression models were fitted with computing hazard ratios (HR and the corresponding 95% confidence intervals (95% CI. Results. 12.77% (36/282 of patients were CIMP-0, 74.1% (209/282 of patients were CIMP-L, and 13.12% (37/282 of patients were CIMP-H. The five-year survival of the 282 CRC patients was 58%. There was significant association between APC gene promoter methylation and CRC overall survival (HR = 1.61; 95% CI: 1.05–2.46; P=0.03. CIMP-H was significantly associated with worse prognosis compared to CIMP-0 (HR = 3.06; 95% CI: 1.19–7.89; P=0.02 and CIMP-L (HR = 1.97; 95% CI: 1.11–3.48; P=0.02, respectively. While comparing with the combine of CIMP-L and CIMP-0 (CIMP-L/0, CIMP-H also presented a worse prognosis (HR = 2.31; 95% CI: 1.02–5.24; P=0.04. Conclusion. CIMP-H may be a predictor of a poor prognosis of CRC in Northeast China patients.

A Novel Approach to model EPIC variable background

Science.gov (United States)

Marelli, M.; De Luca, A.; Salvetti, D.; Belfiore, A.

2017-10-01

One of the main aim of the EXTraS (Exploring the X-ray Transient and variable Sky) project is to characterise the variability of serendipitous XMM-Newton sources within each single observation. Unfortunately, 164 Ms out of the 774 Ms of cumulative exposure considered (21%) are badly affected by soft proton flares, hampering any classical analysis of field sources. De facto, the latest releases of the 3XMM catalog, as well as most of the analysis in literature, simply exclude these 'high background' periods from analysis. We implemented a novel SAS-indipendent approach to produce background-subtracted light curves, which allows to treat the case of very faint sources and very bright proton flares. EXTraS light curves of 3XMM-DR5 sources will be soon released to the community, together with new tools we are developing.

Who's in and who's out: Labour law and those excluded from its ...

African Journals Online (AJOL)

The alternative is to challenge the divisions by organising the workers who are excluded at present. Significant gains can be made, it suggests, by working in parallel with other organisations, including those mobilising in the informal economy. The starting point, however, is in the workplaces where their own members are ...

MHD flow of Powell-Eyring nanofluid over a non-linear stretching sheet with variable thickness

Directory of Open Access Journals (Sweden)

T. Hayat

Full Text Available This research explores the magnetohydrodynamic (MHD boundary layer flow of Powell-Eyring nanofluid past a non-linear stretching sheet of variable thickness. An electrically conducting fluid is considered under the characteristics of magnetic field applied transverse to the sheet. The mathematical expressions are accomplished via boundary layer access, Brownian motion and thermophoresis phenomena. The flow analysis is subjected to a recently established conditions requiring zero nanoparticles mass flux. Adequate transformations are implemented for the reduction of partial differential systems to the ordinary differential systems. Series solutions for the governing nonlinear flow of momentum, temperature and nanoparticles concentration have been executed. Physical interpretation of numerous parameters is assigned by graphical illustrations and tabular values. Moreover the numerical data of drag coefficient and local heat transfer rate are executed and discussed. It is investigated that higher wall thickness parameter results in the reduction of velocity distribution. Effects of thermophoresis parameter on temperature and concentration profiles are qualitatively similar. Both the temperature and concentration profiles are enhanced for higher values of thermophoresis parameter. Keywords: MHD, Variable thicked surface, Powell-Eyring nanofluid, Zero mass flux conditions

Non-aneurysmal subarachnoid hemorrhage

DEFF Research Database (Denmark)

Bashir, Asma; Mikkelsen, Ronni; Sørensen, Leif

2017-01-01

Purpose Repeat imaging in patients with non-aneurysmal subarachnoid hemorrhage (NASAH) remains controversial. We aim to report our experience with NASAH with different hemorrhage patterns, and to investigate the need for further diagnostic workup to determine the underlying cause of hemorrhage. M...... adequate with absence of hematoma and vasospasm. In contrast, a follow-up DSA should be mandatory for confirming or excluding vascular pathology in case of nPMSAH in order to prevent rebleeding....

Benthic diatom community response to environmental variables and metal concentrations in a contaminated bay adjacent to Casey Station, Antarctica

International Nuclear Information System (INIS)

Cunningham, Laura; Snape, Ian; Stark, Jonathan S.; Riddle, Martin J.

2005-01-01

This study examined the effects of anthropogenic contaminants and environmental variables on the composition of benthic diatom communities within a contaminated bay adjacent to an abandoned waste disposal site in Antarctica. The combination of geographical, environmental and chemical data included in the study explained all of the variation observed within the diatom communities. The chemical data, particularly metal concentrations, explained 45.9% of variation in the diatom communities, once the effects of grain-size and spatial structure had been excluded. Of the metals, tin explained the greatest proportion of variation in the diatom communities (28%). Tin was very highly correlated (R 2 > 0.95) with several other variables (copper, iron, lead, and sum of metals), all of which explained similarly high proportions of total variation. Grain-size data explained 23% of variation once the effects of spatial structure and the chemical data had been excluded. The pure spatial component explained only 1.8% of the total variance. The study demonstrates that much of the compositional variability observed in the bay can be explained by concentrations of metal contaminants

Floating-bioadhesive gastroretentive Caesalpinia pulcherrima-based beads of amoxicillin trihydrate for Helicobacter pylori eradication.

Science.gov (United States)

Thombre, Nilima A; Gide, Paraag S

2016-01-01

An oral dosage form containing floating bioadhesive gastroretentive microspheres forms a stomach-specific drug delivery system for the treatment of Helicobacter pylori. To prepare and evaluate controlled release floating bioadhesive gastroretentive chitosan-coated amoxicillin trihydrate-loaded Caesalpinia pulcherrima galactomannan (CPG)-alginate beads (CCA-CPG-A), for H. pylori eradication. CCA-CPG-A beads were prepared by ionotropic gelation, using 2(3) factorial design with quantity of drug, combination of CPG with sodium alginate and concentration of calcium chloride as variables. Beads facilitated mucoadhesion to gastric mucosa with floating nature caused by chitosan coating for wide distribution throughout GIT. Developed beads were evaluated for characteristics like beads size-morphology, entrapment efficiency, DSC, XRD, FTIR, swelling ratio, in vitro mucoadhesion, in vitro drug release, in vitro floating and in vitro H. pylori growth inhibition studies. CCA-CPG-A beads were studied in Wistar rats for in vivo gastric mucoadhesion, in vivo H. pylori growth inhibition studies using PCR amplification of isolated DNA, rapid urease test. Developed beads possess drug release of 79-92%, entrapment efficiency of 65-89%, mucoadhesion of 61-89%. In vivo mucoadhesion study showed more than 85% mucoadhesion of beads even after 7th hour. In vitro-in vivo growth inhibition study showed complete eradication of H. pylori. CPG-alginate and chitosan in beads interacts with gastric mucosubstrate surface for prolonged gastric residence with floating bioadhesion mechanism for H. pylori eradication in rats. Floating bioadhesive CCA-CPG-A beads offer a promising drug delivery system for H. pylori eradication at lower dose, reduced adverse effect and enhance bioavailability.

24 CFR 203.18c - One-time or up-front mortgage insurance premium excluded from limitations on maximum mortgage...

Science.gov (United States)

2010-04-01

... insurance premium excluded from limitations on maximum mortgage amounts. 203.18c Section 203.18c Housing and...-front mortgage insurance premium excluded from limitations on maximum mortgage amounts. After... LOAN INSURANCE PROGRAMS UNDER NATIONAL HOUSING ACT AND OTHER AUTHORITIES SINGLE FAMILY MORTGAGE...

Sex differences in DNA methylation of the cord blood are related to sex-bias psychiatric diseases

Science.gov (United States)

Maschietto, Mariana; Bastos, Laura Caroline; Tahira, Ana Carolina; Bastos, Elen Pereira; Euclydes, Veronica Luiza Vale; Brentani, Alexandra; Fink, Günther; de Baumont, Angelica; Felipe-Silva, Aloísio; Francisco, Rossana Pulcineli Vieira; Gouveia, Gisele; Grisi, Sandra Josefina Ferraz Ellero; Escobar, Ana Maria Ulhoa; Moreira-Filho, Carlos Alberto; Polanczyk, Guilherme Vanoni; Miguel, Euripedes Constantino; Brentani, Helena

2017-03-01

Sex differences in the prevalence of psychiatric disorders are well documented, with exposure to stress during gestation differentially impacting females and males. We explored sex-specific DNA methylation in the cord blood of 39 females and 32 males born at term and with appropriate weight at birth regarding their potential connection to psychiatric outcomes. Mothers were interviewed to gather information about environmental factors (gestational exposure) that could interfere with the methylation profiles in the newborns. Bisulphite converted DNA was hybridized to Illumina HumanMethylation450 BeadChips. Excluding XYS probes, there were 2,332 differentially methylated CpG sites (DMSs) between sexes, which were enriched within brain modules of co-methylated CpGs during brain development and also differentially methylated in the brains of boys and girls. Genes associated with the DMSs were enriched for neurodevelopmental disorders, particularly for CpG sites found differentially methylated in brain tissue between patients with schizophrenia and controls. Moreover, the DMS had an overlap of 890 (38%) CpG sites with a cohort submitted to toxic exposition during gestation. This study supports the evidences that sex differences in DNA methylation of autosomes act as a primary driver of sex differences that are found in psychiatric outcomes.

Behavioral Variables Associated with Obesity in Police Officers

OpenAIRE

CAN, S. Hakan; HENDY, Helen M.

2014-01-01

Past research has documented that non-behavioral variables (such as long work hours, exposure to police stressors) are associated with obesity risk in police officers, but limited research has examined behavioral variables that might be targeted by Employee Assistance Programs for police weight management. The present study compared non-obese and obese officers for behavioral variables found associated with obesity in other adult samples: physical activity (cardiovascular, strength-training, ...

The usefulness of the Basic Question Procedure for determining non-response bias in substantive variables - A test of four telephone questionnaires

NARCIS (Netherlands)

van Goor, H.; van Goor, A.

2007-01-01

The Basic Question Procedure (BQP) is a method for determining non-response bias. The BQP involves asking one basic question - that is, the question relating to the central substantive variable of the study - of those persons who refuse to participate in the survey. We studied the usefulness of this

Adverse prognostic impact of the CpG island methylator phenotype in metastatic colorectal cancer.

Science.gov (United States)

Cha, Yongjun; Kim, Kyung-Ju; Han, Sae-Won; Rhee, Ye Young; Bae, Jeong Mo; Wen, Xianyu; Cho, Nam-Yun; Lee, Dae-Won; Lee, Kyung-Hun; Kim, Tae-Yong; Oh, Do-Youn; Im, Seock-Ah; Bang, Yung-Jue; Jeong, Seung-Yong; Park, Kyu Joo; Kang, Gyeong Hoon; Kim, Tae-You

2016-07-12

The association between the CpG island methylator phenotype (CIMP) and clinical outcomes in metastatic colorectal cancer remains unclear. We investigated the prognostic impact of CIMP in patients with metastatic colorectal cancer treated with systemic chemotherapy. Eight CIMP-specific promoters (CACNA1G, IGF2, NEUROG1, RUNX3, SOCS1, CDKN2A, CRABP1, and MLH1) were examined. The CIMP status was determined by the number of methylated promoters as high (⩾5), low (1-4), and negative (0). A total of 153 patients were included (men/women, 103/50; median age, 61 years; range, 22-80 years). The CIMP status was negative/low/high in 77/ 69/7 patients, respectively. Overall survival (OS) was significantly different among the three CIMP groups, with median values of 35.7, 22.2, and 9.77 months for the negative, low, and high groups, respectively (PCIMP groups; the median OS was 37.9, 23.8, and 6.77 months for the negative, low, and high groups, respectively (PCIMP groups (53.4% vs 45.1% vs 16.7%, respectively; P=0.107). For patients treated with fluoropyrimidine and irinotecan second-line chemotherapy (N=86), only OS showed a difference according to the CIMP status, with median values of 20.4, 13.4, and 2.90 months for the negative, low, and high groups, respectively (PCIMP status is a negative prognostic factor for patients with metastatic colorectal cancer treated with chemotherapy.

GUILT OF PERSONS WITH MENTAL DISORDERS ARE NOT EXCLUDING RESPONSIBILITIES

OpenAIRE

Ekaterina Valerievna Yurchak

2014-01-01

In the theory of law as a key cross-sectoral and multi-disciplinary institutions is the Institute of guilt. At the present stage of development of the law, in a convergence of many of its branches, it is important to investigate exhaustively the institution with the general legal position, both in general and in particular - the situation of the guilt of persons with mental disorder, not excluding sanity.The purpose of this study - to investigate the situation of the fault of persons with a m...

Evaluation of CpG Island Methylator Phenotype as a Biomarker in Colorectal Cancer Treated With Adjuvant Oxaliplatin.

Science.gov (United States)

Cohen, Stacey A; Wu, Chen; Yu, Ming; Gourgioti, Georgia; Wirtz, Ralph; Raptou, Georgia; Gkakou, Chryssa; Kotoula, Vassiliki; Pentheroudakis, George; Papaxoinis, George; Karavasilis, Vasilios; Pectasides, Dimitrios; Kalogeras, Konstantine T; Fountzilas, George; Grady, William M

2016-06-01

The CpG island methylator phenotype (CIMP) is a promising biomarker for irinotecan/5-fluorouracil/leucovorin chemotherapy for stage III colon cancer. In the present study, we evaluated whether CIMP is a prognostic biomarker for standard-of-care oxaliplatin-based adjuvant therapy. The HE6C/05 trial randomized 441 patients with stage II-III colorectal adenocarcinoma to adjuvant XELOX (capecitabine, oxaliplatin) or modified FOLFOX6 (5-fluorouracil, leucovorin, oxaliplatin). The primary and secondary objectives were disease-free and overall survival, respectively. CIMP status was determined using the DNA methylation status of CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS1. Cox models were used to assess the association of CIMP with survival. Of the 293 available tumors, 28 (9.6%) were CIMP(+). On univariate Cox regression analysis, no significant differences in survival were observed between individuals with CIMP(+) versus CIMP(-) tumors. CIMP(+) tumors were more likely to be right-sided and BRAF mutant (χ(2), P CIMP did not appear to be a prognostic biomarker in oxaliplatin-treated patients with resected colorectal cancer. Copyright © 2015 Elsevier Inc. All rights reserved.

Technique for determining cesium-137 in milk excluding ashing

International Nuclear Information System (INIS)

Antonova, V.A.; Prokof'ev, O.N.

1984-01-01

For the purpose of simplification of the method of milk sample preparation for the radiochemical analysis for 137 Cs in laboratory sanitary and higienic investigations rapid analysis technique excluding sample ashing is developed. The technique comprises sample mixing with silica gel during an hour, 137 Cs desorption from silica gel into the 1N solution of hydrochloric acid, radiochemical analysis of hydrochloric solution for determining 137 Cs. The comparison of the results obtained by the above method and that with ashing provides perfect agreement. For taking into account the incompleteness of 137 Cs adsorption by silica gel a correction factor is applied in calculation formulae

NUMERICAL ALGORITHMS AT NON-ZERO CHEMICAL POTENTIAL. PROCEEDINGS OF RIKEN BNL RESEARCH CENTER WORKSHOP, VOLUME 19

International Nuclear Information System (INIS)

Blum, T.; Creutz, M.

1999-01-01

The RIKEN BNL Research Center hosted its 19th workshop April 27th through May 1, 1999. The topic was Numerical Algorithms at Non-Zero Chemical Potential. QCD at a non-zero chemical potential (non-zero density) poses a long-standing unsolved challenge for lattice gauge theory. Indeed, it is the primary unresolved issue in the fundamental formulation of lattice gauge theory. The chemical potential renders conventional lattice actions complex, practically excluding the usual Monte Carlo techniques which rely on a positive definite measure for the partition function. This ''sign'' problem appears in a wide range of physical systems, ranging from strongly coupled electronic systems to QCD. The lack of a viable numerical technique at non-zero density is particularly acute since new exotic ''color superconducting'' phases of quark matter have recently been predicted in model calculations. A first principles confirmation of the phase diagram is desirable since experimental verification is not expected soon. At the workshop several proposals for new algorithms were made: cluster algorithms, direct simulation of Grassman variables, and a bosonization of the fermion determinant. All generated considerable discussion and seem worthy of continued investigation. Several interesting results using conventional algorithms were also presented: condensates in four fermion models, SU(2) gauge theory in fundamental and adjoint representations, and lessons learned from strong; coupling, non-zero temperature and heavy quarks applied to non-zero density simulations

Comparing Facebook Users and Facebook Non-Users: Relationship between Personality Traits and Mental Health Variables ? An Exploratory Study

OpenAIRE

Brailovskaia, Julia; Margraf, J?rgen

2016-01-01

Over one billion people use Facebook as a platform for social interaction and self-presentation making it one of the most popular online sites. The aim of the present study was to investigate differences in various personality traits and mental health variables between Facebook users and people who do not use this platform. The data of 945 participants (790 Facebook users, 155 Facebook non-users) were collected. Results indicate that Facebook users score significantly higher on narcissism, se...

Centile estimation for a proportion response variable.

Science.gov (United States)

Hossain, Abu; Rigby, Robert; Stasinopoulos, Mikis; Enea, Marco

2016-03-15

This paper introduces two general models for computing centiles when the response variable Y can take values between 0 and 1, inclusive of 0 or 1. The models developed are more flexible alternatives to the beta inflated distribution. The first proposed model employs a flexible four parameter logit skew Student t (logitSST) distribution to model the response variable Y on the unit interval (0, 1), excluding 0 and 1. This model is then extended to the inflated logitSST distribution for Y on the unit interval, including 1. The second model developed in this paper is a generalised Tobit model for Y on the unit interval, including 1. Applying these two models to (1-Y) rather than Y enables modelling of Y on the unit interval including 0 rather than 1. An application of the new models to real data shows that they can provide superior fits. Copyright © 2015 John Wiley & Sons, Ltd.

Predicting DNA Methylation State of CpG Dinucleotide Using Genome Topological Features and Deep Networks.

Science.gov (United States)

Wang, Yiheng; Liu, Tong; Xu, Dong; Shi, Huidong; Zhang, Chaoyang; Mo, Yin-Yuan; Wang, Zheng

2016-01-22

The hypo- or hyper-methylation of the human genome is one of the epigenetic features of leukemia. However, experimental approaches have only determined the methylation state of a small portion of the human genome. We developed deep learning based (stacked denoising autoencoders, or SdAs) software named "DeepMethyl" to predict the methylation state of DNA CpG dinucleotides using features inferred from three-dimensional genome topology (based on Hi-C) and DNA sequence patterns. We used the experimental data from immortalised myelogenous leukemia (K562) and healthy lymphoblastoid (GM12878) cell lines to train the learning models and assess prediction performance. We have tested various SdA architectures with different configurations of hidden layer(s) and amount of pre-training data and compared the performance of deep networks relative to support vector machines (SVMs). Using the methylation states of sequentially neighboring regions as one of the learning features, an SdA achieved a blind test accuracy of 89.7% for GM12878 and 88.6% for K562. When the methylation states of sequentially neighboring regions are unknown, the accuracies are 84.82% for GM12878 and 72.01% for K562. We also analyzed the contribution of genome topological features inferred from Hi-C. DeepMethyl can be accessed at http://dna.cs.usm.edu/deepmethyl/.

Providing a non-deterministic representation of spatial variability of precipitation in the Everest region

Directory of Open Access Journals (Sweden)

J. Eeckman

2017-09-01

Full Text Available This paper provides a new representation of the effect of altitude on precipitation that represents spatial and temporal variability in precipitation in the Everest region. Exclusive observation data are used to infer a piecewise linear function for the relation between altitude and precipitation and significant seasonal variations are highlighted. An original ensemble approach is applied to provide non-deterministic water budgets for middle and high-mountain catchments. Physical processes at the soil–atmosphere interface are represented through the Interactions Soil–Biosphere–Atmosphere (ISBA surface scheme. Uncertainties associated with the model parametrization are limited by the integration of in situ measurements of soils and vegetation properties. Uncertainties associated with the representation of the orographic effect are shown to account for up to 16 % of annual total precipitation. Annual evapotranspiration is shown to represent 26 % ± 1 % of annual total precipitation for the mid-altitude catchment and 34% ± 3 % for the high-altitude catchment. Snowfall contribution is shown to be neglectable for the mid-altitude catchment, and it represents up to 44 % ± 8 % of total precipitation for the high-altitude catchment. These simulations on the local scale enhance current knowledge of the spatial variability in hydroclimatic processes in high- and mid-altitude mountain environments.

CpGislandEVO: A Database and Genome Browser for Comparative Evolutionary Genomics of CpG Islands

Directory of Open Access Journals (Sweden)

Guillermo Barturen

2013-01-01

Full Text Available Hypomethylated, CpG-rich DNA segments (CpG islands, CGIs are epigenome markers involved in key biological processes. Aberrant methylation is implicated in the appearance of several disorders as cancer, immunodeficiency, or centromere instability. Furthermore, methylation differences at promoter regions between human and chimpanzee strongly associate with genes involved in neurological/psychological disorders and cancers. Therefore, the evolutionary comparative analyses of CGIs can provide insights on the functional role of these epigenome markers in both health and disease. Given the lack of specific tools, we developed CpGislandEVO. Briefly, we first compile a database of statistically significant CGIs for the best assembled mammalian genome sequences available to date. Second, by means of a coupled browser front-end, we focus on the CGIs overlapping orthologous genes extracted from OrthoDB, thus ensuring the comparison between CGIs located on truly homologous genome segments. This allows comparing the main compositional features between homologous CGIs. Finally, to facilitate nucleotide comparisons, we lifted genome coordinates between assemblies from different species, which enables the analysis of sequence divergence by direct count of nucleotide substitutions and indels occurring between homologous CGIs. The resulting CpGislandEVO database, linking together CGIs and single-cytosine DNA methylation data from several mammalian species, is freely available at our website.

CpG island methylator phenotype identifies high risk patients among microsatellite stable BRAF mutated colorectal cancers.

Science.gov (United States)

Vedeld, Hege Marie; Merok, Marianne; Jeanmougin, Marine; Danielsen, Stine A; Honne, Hilde; Presthus, Gro Kummeneje; Svindland, Aud; Sjo, Ole H; Hektoen, Merete; Eknaes, Mette; Nesbakken, Arild; Lothe, Ragnhild A; Lind, Guro E

2017-09-01

The prognostic value of CpG island methylator phenotype (CIMP) in colorectal cancer remains unsettled. We aimed to assess the prognostic value of this phenotype analyzing a total of 1126 tumor samples obtained from two Norwegian consecutive colorectal cancer series. CIMP status was determined by analyzing the 5-markers CAGNA1G, IGF2, NEUROG1, RUNX3 and SOCS1 by quantitative methylation specific PCR (qMSP). The effect of CIMP on time to recurrence (TTR) and overall survival (OS) were determined by uni- and multivariate analyses. Subgroup analyses were conducted according to MSI and BRAF mutation status, disease stage, and also age at time of diagnosis (CIMP positive tumors demonstrated significantly shorter TTR and worse OS compared to those with CIMP negative tumors (multivariate hazard ratio [95% CI] 1.86 [1.31-2.63] and 1.89 [1.34-2.65], respectively). In stratified analyses, CIMP tumors showed significantly worse outcome among patients with microsatellite stable (MSS, P CIMP is significantly associated with inferior outcome for colorectal cancer patients, and can stratify the poor prognostic patients with MSS BRAF mutated tumors. © 2017 The Authors International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.

Comparison of CpG island methylator phenotype (CIMP) frequency in colon cancer using different probe- and gene-specific scoring alternatives on recommended multi-gene panels.

Science.gov (United States)

Berg, Marianne; Hagland, Hanne R; Søreide, Kjetil

2014-01-01

In colorectal cancer a distinct subgroup of tumours demonstrate the CpG island methylator phenotype (CIMP). However, a consensus of how to score CIMP is not reached, and variation in definition may influence the reported CIMP prevalence in tumours. Thus, we sought to compare currently suggested definitions and cut-offs for methylation markers and how they influence CIMP classification in colon cancer. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA), with subsequent fragment analysis, was used to investigate methylation of tumour samples. In total, 31 CpG sites, located in 8 different genes (RUNX3, MLH1, NEUROG1, CDKN2A, IGF2, CRABP1, SOCS1 and CACNA1G) were investigated in 64 distinct colon cancers and 2 colon cancer cell lines. The Ogino gene panel includes all 8 genes, in addition to the Weisenberger panel of which only 5 of the 8 genes included were investigated. In total, 18 alternative combinations of scoring of CIMP positivity on probe-, gene-, and panel-level were analysed and compared. For 47 samples (71%), the CIMP status was constant and independent of criteria used for scoring; 34 samples were constantly scored as CIMP negative, and 13 (20%) consistently scored as CIMP positive. Only four of 31 probes (13%) investigated showed no difference in the numbers of positive samples using the different cut-offs. Within the panels a trend was observed that increasing the gene-level stringency resulted in a larger difference in CIMP positive samples than increasing the probe-level stringency. A significant difference between positive samples using 'the most stringent' as compared to 'the least stringent' criteria (20% vs 46%, respectively; pCIMP depending on the cut-offs and genes included in a panel was found, with twice as many positives samples by least compared to most stringent definition used.

HLA region excluded by linkage analyses of early onset periodontitis

Energy Technology Data Exchange (ETDEWEB)

Sun, C.; Wang, S.; Lopez, N.

1994-09-01

Previous studies suggested that HLA genes may influence susceptibility to early-onset periodontitis (EOP). Segregation analyses indicate that EOP may be due to a single major gene. We conducted linkage analyses to assess possible HLA effects on EOP. Fifty families with two or more close relatives affected by EOP were ascertained in Virginia and Chile. A microsatellite polymorphism within the HLA region (at the tumor necrosis factor beta locus) was typed using PCR. Linkage analyses used a donimant model most strongly supported by previous studies. Assuming locus homogeneity, our results exclude a susceptibility gene within 10 cM on either side of our marker locus. This encompasses all of the HLA region. Analyses assuming alternative models gave qualitatively similar results. Allowing for locus heterogeneity, our data still provide no support for HLA-region involvement. However, our data do not statistically exclude (LOD <-2.0) hypotheses of disease-locus heterogeneity, including models where up to half of our families could contain an EOP disease gene located in the HLA region. This is due to the limited power of even our relatively large collection of families and the inherent difficulties of mapping genes for disorders that have complex and heterogeneous etiologies. Additional statistical analyses, recruitment of families, and typing of flanking DNA markers are planned to more conclusively address these issues with respect to the HLA region and other candidate locations in the human genome. Additional results for markers covering most of the human genome will also be presented.

Collective variables and dissipation

International Nuclear Information System (INIS)

Balian, R.

1984-09-01

This is an introduction to some basic concepts of non-equilibrium statistical mechanics. We emphasize in particular the relevant entropy relative to a given set of collective variables, the meaning of the projection method in the Liouville space, its use to establish the generalized transport equations for these variables, and the interpretation of dissipation in the framework of information theory

Combined effect of thermal dispersion and variable viscosity of non-darcy convection heat transfer in a fluidsaturated porous medium

KAUST Repository

El-Amin, Mohamed

2013-01-01

In this paper, the effects of thermal dispersion and variable viscosity on the non-Darcy free, mixed, and forced convection heat transfer along a vertical flat plate embedded in a fluid-saturated porous medium are investigated. Forchheimer extension is employed in the flow equation to express the non-Darcy model. The fluid viscosity varies as an inverse linear function of temperature. The coefficient of thermal diffusivity has been assumed to be the sum of the molecular diffusivity and the dynamic diffusivity due to mechanical dispersion. Similarity solutions of the governing equations, for an isothermally heated plate, are obtained. Effects of the physical parameters, which govern the problem, on the rate of heat transfer in terms of Nusselt number, the slip velocity, and the boundary layer thickness, for the two cases Darcy and non-Darcy, are shown on graphs or entered in tables. © 2013 by Begell House, Inc.

Quark-nuclear hybrid star equation of state with excluded volume effects

Science.gov (United States)

Kaltenborn, Mark Alexander Randolph; Bastian, Niels-Uwe Friedrich; Blaschke, David Bernhard

2017-09-01

A two-phase description of the quark-nuclear matter hybrid equation of state that takes into account the effect of excluded volume in both the hadronic and the quark-matter phases is introduced. The nuclear phase manifests a reduction of the available volume as density increases, leading to a stiffening of the matter. The quark-matter phase displays a reduction of the effective string tension in the confining density functional from available volume contributions. The nuclear equation of state is based upon the relativistic density-functional model DD2 with excluded volume. The quark-matter equation of state is based upon a quasiparticle model derived from a relativistic density-functional approach and will be discussed in greater detail. The interactions are decomposed into mean scalar and vector components. The scalar interaction is motivated by a string potential between quarks, whereas the vector interaction potential is motivated by higher-order interactions of quarks leading to an increased stiffening at high densities. As an application, we consider matter under compact star constraints of electric neutrality and β equilibrium. We obtain mass-radius relations for hybrid stars that form a third family, disconnected from the purely hadronic star branch, and fulfill the 2 M⊙ constraint.

Intrinsic neuromodulation in the Tritonia swim CPG: serotonin mediates both neuromodulation and neurotransmission by the dorsal swim interneurons.

Science.gov (United States)

Katz, P S; Frost, W N

1995-12-01

1. Neuromodulation has previously been shown to be intrinsic to the central pattern generator (CPG) circuit that generates the escape swim of the nudibranch mollusk Tritonia diomedea; the dorsal swim interneurons (DSIs) make conventional monosynaptic connections and evoke neuromodulatory effects within the swim motor circuit. The conventional synaptic potentials evoked by a DSI onto cerebral neuron 2 (C2) and onto the dorsal flexion neurons (DFNs) consist of a fast excitatory postsynaptic potential (EPSP) followed by a prolonged slow EPSP. In their neuromodulatory role, the DSIs produce an enhancement of the monosynaptic connections made by C2 onto other CPG circuit interneurons and onto efferent flexion neurons. Previous work showed that the DSIs are immunoreactive for serotonin. Here we provide evidence that both the neurotransmission and the neuromodulation evoked by the DSIs are produced by serotonin, and that these effects may be pharmacologically separable. 2. Previously it was shown that bath-applied serotonin both mimics and occludes the modulation of the C2 synapses by the DSIs. Here we find that pressure-applied puffs of serotonin mimic both the fast and slow EPSPs evoked by a DSI onto a DFN, whereas high concentrations of bath-applied serotonin occlude both of these synaptic components. 3. Consistent with the hypothesis that serotonin mediates the actions of the DSIs, the serotonin reuptake inhibitor imipramine prolongs the duration of the fast DSI-DFN EPSP, increases the amplitude of the slow DSI-DFN EPSP, and increases both the amplitude and duration of the modulation of the C2-DFN synapse by the DSIs. 4. Two serotonergic antagonists were found that block the actions of the DSIs. Gramine blocks the fast DSI-DFN EPSP, and has far less of an effect on the slow EPSP and the modulation. Gramine also diminishes the depolarization evoked by pressure-applied serotonin, showing that it is a serotonin antagonist in this system. In contrast, methysergide greatly

Phase II study of nab-paclitaxel in refractory small bowel adenocarcinoma and CpG island methylator phenotype (CIMP)-high colorectal cancer.

Science.gov (United States)

Overman, M J; Adam, L; Raghav, K; Wang, J; Kee, B; Fogelman, D; Eng, C; Vilar, E; Shroff, R; Dasari, A; Wolff, R; Morris, J; Karunasena, E; Pisanic, R; Azad, N; Kopetz, S

2018-01-01

Hypermethylation of promoter CpG islands [CpG island methylator phenotype (CIMP)] represents a unique pathway for the development of colorectal cancer (CRC), characterized by lack of chromosomal instability and a low rate of adenomatous polyposis coli (APC) mutations, which have both been correlated with taxane resistance. Similarly, small bowel adenocarcinoma (SBA), a rare tumor, also has a low rate of APC mutations. This phase II study evaluated taxane sensitivity in SBA and CIMP-high CRC. The primary objective was Response Evaluation Criteria in Solid Tumors version 1.1 response rate. Eligibility included Eastern Cooperative Oncology Group performance status 0/1, refractory disease, and SBA or CIMP-high metastatic CRC. Nab-paclitaxel was initially administered at a dose of 260 mg/m2 every 3 weeks but was reduced to 220 mg/m2 owing to toxicity. A total of 21 patients with CIMP-high CRC and 13 with SBA were enrolled from November 2012 to October 2014. The efficacy-assessable population (patients who received at least three doses of the treatment) comprised 15 CIMP-high CRC patients and 10 SBA patients. Common grade 3 or 4 toxicities were fatigue (12%), neutropenia (9%), febrile neutropenia (9%), dehydration (6%), and thrombocytopenia (6%). No responses were seen in the CIMP-high CRC cohort and two partial responses were seen in the SBA cohort. Median progression-free survival was significantly greater in the SBA cohort than in the CIMP-high CRC cohort (3.2 months compared with 2.1 months, P = 0.03). Neither APC mutation status nor CHFR methylation status correlated with efficacy in the CIMP-high CRC cohort. In vivo testing of paclitaxel in an SBA patient-derived xenograft validated the activity of taxanes in this disease type. Although preclinical studies suggested taxane sensitivity was associated with chromosomal stability and wild-type APC, we found that nab-paclitaxel was inactive in CIMP-high metastatic CRC. Nab-paclitaxel may represent a novel

The application of methylation specific electrophoresis (MSE) to DNA methylation analysis of the 5' CpG island of mucin in cancer cells

International Nuclear Information System (INIS)

Yokoyama, Seiya; Yonezawa, Suguru; Kitamoto, Sho; Yamada, Norishige; Houjou, Izumi; Sugai, Tamotsu; Nakamura, Shin-ichi; Arisaka, Yoshifumi; Takaori, Kyoichi; Higashi, Michiyo

2012-01-01

Methylation of CpG sites in genomic DNA plays an important role in gene regulation and especially in gene silencing. We have reported mechanisms of epigenetic regulation for expression of mucins, which are markers of malignancy potential and early detection of human neoplasms. Epigenetic changes in promoter regions appear to be the first step in expression of mucins. Thus, detection of promoter methylation status is important for early diagnosis of cancer, monitoring of tumor behavior, and evaluating the response of tumors to targeted therapy. However, conventional analytical methods for DNA methylation require a large amount of DNA and have low sensitivity. Here, we report a modified version of the bisulfite-DGGE (denaturing gradient gel electrophoresis) using a nested PCR approach. We designated this method as methylation specific electrophoresis (MSE). The MSE method is comprised of the following steps: (a) bisulfite treatment of genomic DNA, (b) amplification of the target DNA by a nested PCR approach and (c) applying to DGGE. To examine whether the MSE method is able to analyze DNA methylation of mucin genes in various samples, we apply it to DNA obtained from state cell lines, ethanol-fixed colonic crypts and human pancreatic juices. The MSE method greatly decreases the amount of input DNA. The lower detection limit for distinguishing different methylation status is < 0.1% and the detectable minimum amount of DNA is 20 pg, which can be obtained from only a few cells. We also show that MSE can be used for analysis of challenging samples such as human isolated colonic crypts or human pancreatic juices, from which only a small amount of DNA can be extracted. The MSE method can provide a qualitative information of methylated sequence profile. The MSE method allows sensitive and specific analysis of the DNA methylation pattern of almost any block of multiple CpG sites. The MSE method can be applied to analysis of DNA methylation status in many different clinical

B vitamins, methionine and alcohol intake and risk of colon cancer in relation to BRAF mutation and CpG island methylator phenotype (CIMP.

Directory of Open Access Journals (Sweden)

Eva S Schernhammer

Full Text Available One-carbon metabolism appears to play an important role in DNA methylation reaction. Evidence suggests that a low intake of B vitamins or high alcohol consumption increases colorectal cancer risk. How one-carbon nutrients affect the CpG island methylator phenotype (CIMP or BRAF mutation status in colon cancer remains uncertain.Utilizing incident colon cancers in a large prospective cohort of women (the Nurses' Health Study, we determined BRAF status (N = 386 and CIMP status (N = 375 by 8 CIMP-specific markers [CACNA1G, CDKN2A (p16, CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1], and 8 other CpG islands (CHFR, HIC1, IGFBP3, MGMT, MINT-1, MINT-31, p14, and WRN. We examined the relationship between intake of one-carbon nutrients and alcohol and colon cancer risk, by BRAF mutation or CIMP status.Higher folate intake was associated with a trend towards low risk of CIMP-low/0 tumors [total folate intake ≥400 µg/day vs. <200 µg/day; the multivariate relative risk = 0.73; 95% CI = 0.53-1.02], whereas total folate intake had no influence on CIMP-high tumor risks (P(heterogeneity = 0.73. Neither vitamin B(6, methionine or alcohol intake appeared to differentially influence risks for CIMP-high and CIMP-low/0 tumors. Using the 16-marker CIMP panel did not substantially alter our results. B vitamins, methionine or alcohol intake did not affect colon cancer risk differentially by BRAF status.This molecular pathological epidemiology study suggests that low level intake of folate may be associated with an increased risk of CIMP-low/0 colon tumors, but not that of CIMP-high tumors. However, the difference between CIMP-high and CIMP-low/0 cancer risks was not statistically significant, and additional studies are necessary to confirm these observations.

Approximate method of calculation of non-equilibrium flow parameters of chemically reacting nitrogen tetroxide in the variable cross-section channels with energy exchange

International Nuclear Information System (INIS)

Bazhin, M.A.; Fedosenko, G.Eh.; Shiryaeva, N.M.; Mal'ko, M.V.

1986-01-01

It is shown that adiabatic non-equilibrium chemically reacting gas flow with energy exchange in a variable cross-section channel may be subdivided into five possible types: 1) quasi-equilibrium flow; 2) flow in the linear region of deviation from equilibrium state; 3) quasi-frozen flow; 4) flow in the linear region of deviation from frozen state; 5) non-equilibrium flow. Criteria of quasi-equilibrium and quazi-frozen flows, including factors of external action of chemically reacting gas on flow, allow to obtain simple but sufficiently reliable approximate method of calculation of flow parameters. The considered method for solving the problem of chemically reacting nitrogen tetroxide in the variable cross-section channel with energy exchange can be used for evaluation of chemical reaction kinetics on the flow parameter in the stages of axial-flow and radial-flow turbines and in another practical problems

Chronic back pain and associated work and non-work variables among farmworkers from Starr County, Texas.

Science.gov (United States)

Shipp, Eva M; Cooper, Sharon P; del Junco, Deborah J; Delclos, George L; Burau, Keith D; Tortolero, Susan; Whitworth, Ryan E

2009-01-01

This study estimated the prevalence of chronic back pain among migrant farmworker family members and identified associated work and non-work variables. Migrant farmworkers (n = 390 from 267 families) from Starr County, Texas were interviewed in their home once a year for 2 years. The original survey included items measuring demographics, smoking, sleep, farm work, and chronic back pain. For this cross-sectional analysis, multi-level logistic regression was used to identify associated work and other variables associated with chronic back pain while accounting for intraclass correlations due to repeated measures and multiple family members. The prevalence of chronic back pain during the last migration season ranged from 9.5% among the youngest children to 33.3% among mothers. Variables significantly associated with chronic back pain were age (odds ratio [OR], 1.03, per year increase), depressive symptoms while migrating (OR, 8.72), fewer than 8 hours of sleep at home in Starr County (OR, 2.26), fairly bad/very bad quality of sleep while migrating (OR, 3.25), sorting crops at work (OR, 0.18), and working tree crops (OR, 11.72). The role of work exposures, depressive symptoms, and sleep in chronic back pain among farmworkers warrants further examination. Refinements in outcome and exposure assessments are also needed given the lack of a standardized case definition and the variety of tasks and crops involved in farm work in the United States.

Trust and cooperation in the public sphere: why Roma people should not be excluded?

Directory of Open Access Journals (Sweden)

Dragoş DRAGOMAN

2014-05-01

Full Text Available The recent political developments in Romania and other Central and East European countries, marked by rising populism and political extremism, shed light on the essential issue of building a free, tolerant and inclusive public sphere, which is willing to let arguments to be decisive instead of power, status, race or wealth. The current tendencies of socially excluding Roma, indiscriminately taken by populists for unjustified social burden and intolerable racial difference, are a warning for more radical political action that could undermine on the long-run the effort to set up a democratic public space. Excluding from start an entire minority would only encourage future exclusions based on ideology, ethnicity or religion, according to the narrow definition populists use to give to the concept of ‘people’.

Grafted polymers with annealed excluded volume : a model for surfactant association in brushes

NARCIS (Netherlands)

Currie, E.P.K.; Fleer, G.J.; Cohen Stuart, M.A.; Borisov, O.V.

2000-01-01

We present an analytical self-consistent-field (SCF) theory for a neutral polymer brush (a layer of long polymer chains end-grafted to a surface) with annealed excluded volume interactions between the monomer units. This model mimics the reversible adsorption of solute molecules or aggregates, such

Play It Again: Neural Responses to Reunion with Excluders Predicted by Attachment Patterns

Science.gov (United States)

White, Lars O.; Wu, Jia; Borelli, Jessica L.; Mayes, Linda C.; Crowley, Michael J.

2013-01-01

Reunion behavior following stressful separations from caregivers is often considered the single most sensitive clue to infant attachment patterns. Extending these ideas to middle childhood/early adolescence, we examined participants' neural responses to reunion with peers who had previously excluded them. We recorded event-related potentials…

Effects of excluding goat herbivory on Acacia tortilis woodland around pastoralist settlements in northwest Kenya

Science.gov (United States)

Oba, Gufu

1998-08-01

Browsing by goats is considered to cause poor tree regeneration and reduced tree growth around settlements throughout the arid zones of sub-Saharan Africa. This study investigated whether excluding goats from Acacia tortilis woodlands increased tree regeneration, current season's shoot growth rates and browse production over a period of 52 months between 1986 and 1990. The study also investigated the effects of climatic variability on tree growth and browse production. Excluding goat herbivory provided no advantage over continuous browsing for juvenile A. tortilis. Trees on the unbrowsed and on browsed transects increased by 22.2 (standard error [SE] ± 0.53) cm·yr -1 and 25.0 (SE ± 0.58) cm·yr -1, respectively. Fewer but longer shoots were produced by trees on the unbrowsed transects, while trees on the browsed transects invested more in shorter shoots. Net total browse production was lower on unbrowsed (1.73 [standard deviation (SD) ± 4.3] t·ha -1·yr -1) than on the browsed (3.03 [SD ± 3.6] t·ha -1 ·yr -1) transects. Biomass production on unbrowsed and browsed transects was closely correlated with rainfall and presumably soil moisture during wet seasons. Relative growth rates (RGR) of current season's shoots in the two treatments did not differ, implying goat herbivory at moderate stocking density (i.e. 13.0 tropical livestock units [TLU]·km -2) stimulated shoot growth. RGR remained positive except on the browsed transects during 1990, a dry year. Goat browsing pressure was moderate. Total biomass loss on unbrowsed transects was 15.5 %·yr -1 compared with 27.7 %·yr -1 on the browsed transects. These findings do not support the notion that goats always destroy young trees around settlements. Goat herbivory at moderate intensity stimulated shoot productivity. However, the results should not be used to generalize all conditions throughout sub-Saharan Africa, let alone the arid zones of northern Kenya. Rather, there is a need to emphasize individual case

Genome-wide, Single-Cell DNA Methylomics Reveals Increased Non-CpG Methylation during Human Oocyte Maturation

Directory of Open Access Journals (Sweden)

Bo Yu

2017-07-01

Full Text Available The establishment of DNA methylation patterns in oocytes is a highly dynamic process marking gene-regulatory events during fertilization, embryonic development, and adulthood. However, after epigenetic reprogramming in primordial germ cells, how and when DNA methylation is re-established in developing human oocytes remains to be characterized. Here, using single-cell whole-genome bisulfite sequencing, we describe DNA methylation patterns in three different maturation stages of human oocytes. We found that while broad-scale patterns of CpG methylation have been largely established by the immature germinal vesicle stage, localized changes continue into later development. Non-CpG methylation, on the other hand, undergoes a large-scale, generalized remodeling through the final stage of maturation, with the net overall result being the accumulation of methylation as oocytes mature. The role of the genome-wide, non-CpG methylation remodeling in the final stage of oocyte maturation deserves further investigation.

Shift of biome patterns due to simulated climate variability and climate change

International Nuclear Information System (INIS)

Claussen, M.

1993-01-01

The variability of simulated equilibrium-response patterns of biomes caused by simulated climate variability and climate shift is analysed. This investigation is based on various realisations of simulated present-day climate and climate shift. It has been found that the difference between biomes computed from three 10-year climatologies and from the corresponding 30-year climatology, simulated by the Hamburg climate model at T21 resolution, amounts to approximately 6% of the total land area, Antarctica excluded. This difference is mainly due to differences in annual moisture availability and winter temperatures. When intercomparing biomes from the 10-year climatologies a 10% difference is seen, but there is no unique difference pattern. In contrast to the interdecadal variability, the shift of conditions favorable for biomes due to a shift in climate in the next 100 years, caused by an increase in sea-surface temperatures and atmospheric CO 2 , reveals a unique trend pattern. It turns out that the strongest and most significant signal is the north-east shift of conditions for boreal biomes. This signal is caused by an increase of annual temperature sums as well as mean temperatures of the coldest and warmest months. Trends in annual moisture availability are of secondary importance globally. Regionally, a decrease in water availability affects biomes in Central and East Europe and an increase of water availability leads to a potential increase in tropical rain forest. In total, all differences amount to roughly 30% of the total land surface, Antarctica excluded. (orig./KW)

Parametric methods outperformed non-parametric methods in comparisons of discrete numerical variables

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Sandvik Leiv

2011-04-01

Full Text Available Abstract Background The number of events per individual is a widely reported variable in medical research papers. Such variables are the most common representation of the general variable type called discrete numerical. There is currently no consensus on how to compare and present such variables, and recommendations are lacking. The objective of this paper is to present recommendations for analysis and presentation of results for discrete numerical variables. Methods Two simulation studies were used to investigate the performance of hypothesis tests and confidence interval methods for variables with outcomes {0, 1, 2}, {0, 1, 2, 3}, {0, 1, 2, 3, 4}, and {0, 1, 2, 3, 4, 5}, using the difference between the means as an effect measure. Results The Welch U test (the T test with adjustment for unequal variances and its associated confidence interval performed well for almost all situations considered. The Brunner-Munzel test also performed well, except for small sample sizes (10 in each group. The ordinary T test, the Wilcoxon-Mann-Whitney test, the percentile bootstrap interval, and the bootstrap-t interval did not perform satisfactorily. Conclusions The difference between the means is an appropriate effect measure for comparing two independent discrete numerical variables that has both lower and upper bounds. To analyze this problem, we encourage more frequent use of parametric hypothesis tests and confidence intervals.

20 CFR 668.650 - Can INA grantees exclude segments of the eligible population?

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2010-04-01

... eligible population? 668.650 Section 668.650 Employees' Benefits EMPLOYMENT AND TRAINING ADMINISTRATION... population? (a) No, INA grantees cannot exclude segments of the eligible population. INA grantees must document in their Two Year Plan that a system is in place to afford all members of the eligible population...

Income non-reporting: implications for health inequalities research.

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Turrell, G

2000-03-01

an income from their own business or partnership, and lowest among the unemployed and those in receipt of a government pension or benefit (which excluded the unemployed). Given that differences in income non-reporting were small to moderate across levels of the education and occupation variables, and that propensity to not report income was greater among higher socioeconomic groups, estimates of the relation between income and health are unlikely to be affected by socioeconomic variability in income non-response. Probability estimates from a logistic regression suggested that higher rates of income non-reporting among employed persons who received their income from a business or partnership were not attributable to socio-economic factors. Rather, it is proposed that these higher rates were attributable to recall effects, or concerns about having one's income information disclosed to taxation authorities. Future studies need to replicate this analysis to determine whether the results can be inferred to other survey and data collection contexts. The analysis should also be extended to include an examination of the relation between socio-economic position and accuracy of income reporting. Little is known about this issue, yet it represents a potential source of bias that may have important implications for studies that investigate the association between income and health.

Analysis of Within-Test Variability of Non-Destructive Test Methods to Evaluate Compressive Strength of Normal Vibrated and Self-Compacting Concretes

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Nepomuceno, Miguel C. S.; Lopes, Sérgio M. R.

2017-10-01

Non-destructive tests (NDT) have been used in the last decades for the assessment of in-situ quality and integrity of concrete elements. An important step in the application of NDT methods concerns to the interpretation and validation of the test results. In general, interpretation of NDT results should involve three distinct phases leading to the development of conclusions: processing of collected data, analysis of within-test variability and quantitative evaluation of property under investigation. The analysis of within-test variability can provide valuable information, since this can be compared with that of within-test variability associated with the NDT method in use, either to provide a measure of the quality control or to detect the presence of abnormal circumstances during the in-situ application. This paper reports the analysis of the experimental results of within-test variability of NDT obtained for normal vibrated concrete and self-compacting concrete. The NDT reported includes the surface hardness test, ultrasonic pulse velocity test, penetration resistance test, pull-off test, pull-out test and maturity test. The obtained results are discussed and conclusions are presented.

Why are people with mental illness excluded from the rational suicide debate?

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