Sample records for clonal inheritance cpg

  1. Inheritance of an epigenetic mark: the CpG DNA methyltransferase 1 is required for de novo establishment of a complex pattern of non-CpG methylation.

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    Valérie Grandjean

    Full Text Available Site-specific methylation of cytosines is a key epigenetic mark of vertebrate DNA. While a majority of the methylated residues are in the symmetrical (meCpG:Gp(meC configuration, a smaller, but significant fraction is found in the CpA, CpT and CpC asymmetric (non-CpG dinucleotides. CpG methylation is reproducibly maintained by the activity of the DNA methyltransferase 1 (Dnmt1 on the newly replicated hemimethylated substrates (meCpG:GpC. On the other hand, establishment and hereditary maintenance of non-CpG methylation patterns have not been analyzed in detail. We previously reported the occurrence of site- and allele-specific methylation at both CpG and non-CpG sites. Here we characterize a hereditary complex of non-CpG methylation, with the transgenerational maintenance of three distinct profiles in a constant ratio, associated with extensive CpG methylation. These observations raised the question of the signal leading to the maintenance of the pattern of asymmetric methylation. The complete non-CpG pattern was reinstated at each generation in spite of the fact that the majority of the sperm genomes contained either none or only one methylated non-CpG site. This observation led us to the hypothesis that the stable CpG patterns might act as blueprints for the maintenance of non-CpG DNA methylation. As predicted, non-CpG DNA methylation profiles were abrogated in a mutant lacking Dnmt1, the enzymes responsible for CpG methylation, but not in mutants defective for either Dnmt3a or Dnmt2.

  2. Clonal propagation

    Energy Technology Data Exchange (ETDEWEB)

    Libby, W.J.


    Cloning promises to be the basis of a revolution in tree improvement with important effects on silviculture, forest policy, forest harvesting, and wood utilization. Grafting and rooting have been the traditional methods. Cell, tissue, and organ culture are newer methods of cloning. The goal is to produce embryoids from cell culture and encapsulate them to produce artificial seeds with high clonal fidelity. When this occurs, it seems likely that the shift to clonal forestry will occur quickly wherever forests are managed as renewable resources.

  3. How clonal are human mitochondria?


    Eyre-Walker, A; Smith, N H; Smith, J.M.


    Phylogenetic trees constructed using human mitochondrial sequences contain a large number of homoplasies. These are due either to repeated mutation or to recombination between mitochondrial lineages. We show that a tree constructed using synonymous variation in the protein coding sequences of 29 largely complete human mitochondrial molecules contains 22 homoplasies at 32 phylogenetically informative sites. This level of homoplasy is very unlikely if inheritance is clonal, even if we take into...

  4. CpG traffic lights are markers of regulatory regions in humans

    KAUST Repository

    Khamis, Abdullah M.


    DNA methylation is involved in regulation of gene expression. Although modern methods profile DNA methylation at single CpG sites, methylation levels are usually averaged over genomic regions in the downstream analyses. In this study we demonstrate that single CpG methylation can serve as a more accurate predictor of gene expression compared to average promoter / gene body methylation. CpG positions with significant correlation between methylation and expression of a gene nearby (named CpG traffic lights) are evolutionary conserved and enriched for exact TSS positions and active enhancers. Among all promoter types, CpG traffic lights are especially enriched in poised promoters. Genes that harbor CpG traffic lights are associated with development and signal transduction. Methylation levels of individual CpG traffic lights vary between cell types dramatically with the increased frequency of intermediate methylation levels, indicating cell population heterogeneity in CpG methylation levels. Being in line with the concept of the inherited stochastic epigenetic variation, methylation of such CpG positions might contribute to transcriptional regulation. Alternatively, one can hypothesize that traffic lights are markers of absent gene expression resulting from inactivation of their regulatory elements. The CpG traffic lights provide a promising insight into mechanisms of enhancer activity and gene regulation linking methylation of single CpG to expression.

  5. Inherited Thrombophilia

    Institute of Scientific and Technical Information of China (English)



    @@ The term thrombophilia includes any inherited and acquired disorders associated with an increased tendency to venous thromboembolism(VTE), the presence of inherited thrombophilic defects exposed carriers to increased risks for VTE compared with noncarriers.


    Institute of Scientific and Technical Information of China (English)

    Zhao Weigong; Han Xuezhe; Li Xinyou; Guo Xong; Liu Miao


    Objective Bacterial DNA is a pathogen-derived molecule which can regulate the innate immune system by stimulating NF-κB activation. The activity of bacterial DNA relies on its content of unmethylated CpG dinucleotides in particular base contexts("CpG motif"). In light of the pivotal role played by NF-κB in osteoclast differentiation, the ability of CpG oligodeoxynucleotides (CpG ODN) coming from bacterial DNA to modulate osteoclastogenesis was studied. Methods Bone marrow mononuclear cells (BMM) were purified from Balb/c mice, cultured in α-MEM media containing 10% FCS in the presence of mouse M-CSF, with either RANKL or ODNs for 5 days. Osteoclast formation was evaluated on day 5 according to TRAP and May-Grunwald-Giemsa staining. Results CpG ODN alone could induce osteoclast formation in the low degree in BMM culture. The relationship between CpG ODN and RANKL was that CpG ODN could inhibit RANKL-induced osteoclastogenesis when present from the beginning of BMM culture, but strongly increased RANKL-induced osteoclastogenesis in RANKL-pretreated BMMs. Conclusion The mechanism of CpG ODN regulating osteoclast differentiation was bidirectional, which might be a potential therapy for treating metabolic bone disease.

  7. Collaborations between CpG sites in DNA methylation (United States)

    Song, You; Ren, Honglei; Lei, Jinzhi


    DNA methylation patterns have profound impacts on genome stability, gene expression and development. The molecular base of DNA methylation patterns has long been focused at single CpG sites level. Here, we construct a kinetic model of DNA methylation with collaborations between CpG sites, from which a correlation function was established based on experimental data. The function consists of three parts that suggest three possible sources of the correlation: movement of enzymes along DNA, collaboration between DNA methylation and nucleosome modification, and global enzyme concentrations within a cell. Moreover, the collaboration strength between DNA methylation and nucleosome modification is universal for mouse early embryo cells. The obtained correlation function provides insightful understanding for the mechanisms of inheritance of DNA methylation patterns.

  8. CpG demethylation enhances alpha-synuclein expression and affects the pathogenesis of Parkinson's disease.

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    Lumine Matsumoto

    Full Text Available BACKGROUND: Alpha-synuclein (SNCA gene expression is an important factor in the pathogenesis of Parkinson's disease (PD. Gene multiplication can cause inherited PD, and promoter polymorphisms that increase SNCA expression are associated with sporadic PD. CpG methylation in the promoter region may also influence SNCA expression. METHODOLOGY/PRINCIPAL FINDINGS: By using cultured cells, we identified a region of the SNCA CpG island in which the methylation status altered along with increased SNCA expression. Postmortem brain analysis revealed regional non-specific methylation differences in this CpG region in the anterior cingulate and putamen among controls and PD; however, in the substantia nigra of PD, methylation was significantly decreased. CONCLUSIONS/SIGNIFICANCE: This CpG region may function as an intronic regulatory element for SNCA gene. Our findings suggest that a novel epigenetic regulatory mechanism controlling SNCA expression influences PD pathogenesis.

  9. To inherit heritage or to inherit inheritance?

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    Vladimir Krivošejev


    Full Text Available The Republic of Serbia is one of the few, if not the only country in the world that, at ratification and translation of the term „baština“– heritage which appears in two significant and related international conventions of UNESCO, used different terms: „baština“– „heritage“, with regard to the Convention Concerning the Protection of the World Cultural and Natural Heritage, and „nasledje“ –inheritance in the Convention for the Safeguarding of the Intangible Cultural Heritage. One of the reasons for the subsequent rejection of the term heritage could lay in the opinion that it was the case of (end of 20th and beginning of the 21st century political bureaucratic introduction of an old, forgotten word, which also contains the notion of gender incorrectness based on pointing out the inheritance through the male line, which could be in conflict with international law. The views expressed in this paper suggest the unsustainability of these claims, as well as greater suitability of the term „baština“– heritage. Namely, the ratification of the Convention Concerning the Protection of the World Cultural and Natural Heritage was done as early as in 1974, and since then the term „baština“– heritage was used, its new introduction into use on the basis of recent daily political aspirations cannot be the case. At the same time inheritance through the male line is encountered with the use of the Latin word „patrimonium“, which is the basis for the terms used in the official translation of the UNESCO-listed conventions in French and Spanish: „patrimoine“ and „patrimonio“ (and other Roman languages so that the use of the term „baština“ –heritage cannot be a violation of international legal norms. Finally, bearing in mind the fact that, in general, use of languages is impossible to achieve complete gender purism, it is necessary to emphasize that in contrast to the term „nasledje“ – inheritance, the

  10. Technology evaluation: CpG-7909, Coley. (United States)

    Paul, Stéphane


    Coley Pharmaceutical (formerly CpG ImmunoPharmaceuticals) is developing CpG-7909 (ProMune) for use in the potential treatment of cancer and as a vaccine adjuvant. By April 2000, CpG-7909 had entered phase I/II trials for cancer and in March 2002, Coley initiated a phase I trial in non-Hodgkin's lymphoma in combination with rituximab (Rituxan). By October 2002, CpG-7909 was in phase II trials as a vaccine adjuvant. Cpg-7909 is currently also undergoing phase II trials for melanoma.

  11. Formulation of vaccines containing CpG oligonucleotides and alum


    Aebig, Joan A.; Mullen, Gregory E. D.; Dobrescu, Gelu; Rausch, Kelly; Lambert, Lynn; Ajose-Popoola, Olubunmi; Long, Carole A.; Saul, Allan; Miles, Aaron P.


    CpG oligodeoxynucleotides are potent immunostimulants. For parenterally delivered alum based vaccines, the immunostimulatory effect of CpG depends on the association of the CpG and antigen to the alum. We describe effects of buffer components on the binding of CPG 7909 to aluminum hydroxide (Alhydrogel), assays for measuring binding of CPG 7909 to alum and CPG 7909 induced dissociation of antigen from the alum. Free CPG 7909 is a potent inducer of IP-10 in mice. However the lack of IP-10 prod...

  12. Formulation of vaccines containing CpG oligonucleotides and alum. (United States)

    Aebig, Joan A; Mullen, Gregory E D; Dobrescu, Gelu; Rausch, Kelly; Lambert, Lynn; Ajose-Popoola, Olubunmi; Long, Carole A; Saul, Allan; Miles, Aaron P


    CpG oligodeoxynucleotides are potent immunostimulants. For parenterally delivered alum-based vaccines, the immunostimulatory effect of CpG depends on the association of the CpG and antigen to the alum. We describe effects of buffer components on the binding of CPG 7909 to aluminum hydroxide (Alhydrogel), assays for measuring binding of CPG 7909 to alum and CPG 7909 induced dissociation of antigen from the alum. Free CPG 7909 is a potent inducer of IP-10 in mice. However the lack of IP-10 production from formulations containing bound CPG 7909 suggested that CPG 7909 does not rapidly dissociate from the alum after injection. It also suggests that IP-10 assays are not a good basis for potency assays for alum-based vaccines containing CPG 7909.

  13. Gender affiliation and inheritance

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    Đorđević Jadranka Đ.


    Full Text Available Looking at the inheritance matter in the socialist period, the author concludes that it was based solely on gender. This paper explains the relationship between gender, inheritance, ownership and possessions among kinsmen in the Vranje district. During the socialist period so called customary law of inheritance (a right to inherit a deceased father, that is, a mother was socially and legislatively accepted. The women from the Vranje district are aware of their unfair position in matters of inheritance, but also they know that even if they are to inherit a property they will not become equal to men. It is obvious that it was an illusion that a socialist organization with its legislative system (or any other, as a mater of fact could establish the gender equality in inheritance and thus solve the dualism between the customary law and the law.

  14. Clonality evaluation in human tissues

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    Villamizar-Rivera, Nicolás


    Full Text Available Malignant proliferations are usually clonal. While most times the biological potential can be established through routine pathologic and clinical examinations, some cases are difficult to classify. Moreover, in some situations there are dominant clones whose analysis is important, such as in autoimmune diseases and immunodeficiency. This paper presents in an understandable way the main techniques for the study of clonality, namely: evaluation of gene rearrangements of antigen receptor, and evaluation of human antigen receptor gene.

  15. Epigenetic Memory as a Basis for Intelligent Behavior in Clonal Plants. (United States)

    Latzel, Vít; Rendina González, Alejandra P; Rosenthal, Jonathan


    Environmentally induced epigenetic change enables plants to remember past environmental interactions. If this memory capability is exploited to prepare plants for future challenges, it can provide a basis for highly sophisticated behavior, considered intelligent by some. Against the backdrop of an overview of plant intelligence, we hypothesize: (1) that the capability of plants to engage in such intelligent behavior increases with the additional level of complexity afforded by clonality, and; (2) that more faithful inheritance of epigenetic information in clonal plants, in conjunction with information exchange and coordination between connected ramets, is likely to enable especially advanced intelligent behavior in this group. We therefore further hypothesize that this behavior provides ecological and evolutionary advantages to clonal plants, possibly explaining, at least in part, their widespread success. Finally, we suggest avenues of inquiry to enable assessing intelligent behavior and the role of epigenetic memory in clonal species.

  16. Relaxing Behavioural Inheritance

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    Nuno Amálio


    Full Text Available Object-oriented (OO inheritance allows the definition of families of classes in a hierarchical way. In behavioural inheritance, a strong version, it should be possible to substitute an object of a subclass for an object of its superclass without any observable effect on the system. Behavioural inheritance is related to formal refinement, but, as observed in the literature, the refinement constraints are too restrictive, ruling out many useful OO subclassings. This paper studies behavioural inheritance in the context of ZOO, an object-oriented style for Z. To overcome refinement's restrictions, this paper proposes relaxations to the behavioural inheritance refinement rules. The work is presented for Z, but the results are applicable to any OO language that supports design-by-contract.

  17. Multi-Dimensional Inheritance

    CERN Document Server

    Erbach, G


    In this paper, we present an alternative approach to multiple inheritance for typed feature structures. In our approach, a feature structure can be associated with several types coming from different hierarchies (dimensions). In case of multiple inheritance a type has supertypes from different hierarchies. We contrast this approach with approaches based on a single type hierarchy where a feature structure has only one unique most general type, and multiple inheritance involves computation of greatest lower bounds in the hierarchy. The proposed approach supports current linguistic analyses in constraint-based formalisms like HPSG, inheritance in the lexicon, and knowledge representation for NLP systems. Finally, we show that multi-dimensional inheritance hierarchies can be compiled into a Prolog term representation, which allows to compute the conjunction of two types efficiently by Prolog term unification.

  18. Uniparental Inheritance Promotes Adaptive Evolution in Cytoplasmic Genomes. (United States)

    Christie, Joshua R; Beekman, Madeleine


    Eukaryotes carry numerous asexual cytoplasmic genomes (mitochondria and plastids). Lacking recombination, asexual genomes should theoretically suffer from impaired adaptive evolution. Yet, empirical evidence indicates that cytoplasmic genomes experience higher levels of adaptive evolution than predicted by theory. In this study, we use a computational model to show that the unique biology of cytoplasmic genomes-specifically their organization into host cells and their uniparental (maternal) inheritance-enable them to undergo effective adaptive evolution. Uniparental inheritance of cytoplasmic genomes decreases competition between different beneficial substitutions (clonal interference), promoting the accumulation of beneficial substitutions. Uniparental inheritance also facilitates selection against deleterious cytoplasmic substitutions, slowing Muller's ratchet. In addition, uniparental inheritance generally reduces genetic hitchhiking of deleterious substitutions during selective sweeps. Overall, uniparental inheritance promotes adaptive evolution by increasing the level of beneficial substitutions relative to deleterious substitutions. When we assume that cytoplasmic genome inheritance is biparental, decreasing the number of genomes transmitted during gametogenesis (bottleneck) aids adaptive evolution. Nevertheless, adaptive evolution is always more efficient when inheritance is uniparental. Our findings explain empirical observations that cytoplasmic genomes-despite their asexual mode of reproduction-can readily undergo adaptive evolution. © The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

  19. Dominantly Inherited Nemaline Myopathy

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    J Gordon Millichap


    Full Text Available A locus on chromosome 15q21-23 for a dominantly inherited nemaline myopathy with core-like lesions is reported in two unrelated families evaluated at University Medical Center, Nijmegen, The Netherlands.

  20. A distinct group of CpG islands shows differential DNA methylation between replicas of the same cell line in vitro. (United States)

    Cocozza, Sergio; Scala, Giovanni; Miele, Gennaro; Castaldo, Imma; Monticelli, Antonella


    CpG dinucleotide-rich genomic DNA regions, known as CpG islands (CGIs), can be methylated at their cytosine residues as an epigenetic mark that is stably inherited during cell mitosis. Differentially methylated regions (DMRs) are genomic regions showing different degrees of DNA methylation in multiple samples. In this study, we focused our attention on CGIs showing different DNA methylation between two culture replicas of the same cell line. We used methylation data of 35 cell lines from the Encyclopedia of DNA Elements (ENCODE) consortium to identify CpG islands that were differentially methylated between replicas of the same cell line and denoted them Inter Replicas Differentially Methylated CpG islands (IRDM-CGIs). We identified a group of IRDM-CGIs that was consistently shared by different cell lines, and denoted it common IRDM-CGIs. X chromosome CGIs were overrepresented among common IRDM-CGIs. Autosomal IRDM-CGIs were preferentially located in gene bodies and intergenic regions had a lower G + C content, a smaller mean length, and a reduced CpG percentage. Functional analysis of the genes associated with autosomal IRDM-CGIs showed that many of them are involved in DNA binding and development. Our results show that several specific functional and structural features characterize common IRDM-CGIs. They may represent a specific subset of CGIs that are more prone to being differentially methylated for their intrinsic characteristics.

  1. Epigenetic memory as a basis for intelligent behaviour in clonal plants

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    Vit Latzel


    Full Text Available Environmentally induced epigenetic change enables plants to remember past environmental interactions. If this memory capability is exploited to prepare plants for future challenges, it can provide a basis for highly sophisticated behaviour, considered intelligent by some. Against the backdrop of an overview of plant intelligence, we hypothesise: 1 that the capability of plants to engage in such intelligent behaviour increases with increasing modularity, and; 2 that more faithful inheritance of epigenetic information in clonal plants, in conjunction with information exchange and coordination between connected ramets, is likely to enable especially advanced intelligent behaviour in this group. We therefore further hypothesise that this behaviour provides ecological and evolutionary advantages to clonal plants, possibly explaining, at least in part, their widespread success. Finally, we suggest experiments that could allow for assessing intelligent behaviour and the role of epigenetic memory in clonal species.

  2. Safe Dynamic Multiple Inheritance

    DEFF Research Database (Denmark)

    Ernst, Erik


    Multiple inheritance and similar mechanisms are usually only supported at compile time in statically typed languages. Nevertheless, dynamic multiple inheritance would be very useful in the development of complex systems, because it allows the creation of many related classes without an explosion...... in the size and level of redundancy in the source code. In fact, dynamic multiple inheritance is already available. The language gbeta is statically typed and has supported run-time combination of classes and methods since 1997, by means of the combination operator '&'. However, with certain combinations...... of operands the '&' operator fails; as a result, dynamic creation of new classes and methods was considered a dangerous operation in all cases. This paper presents a large and useful category of combinations, and proves that combinations in this category will always succeed....

  3. Organs as inheritable property? (United States)

    Voo, Teck Chuan; Holm, Soren


    It has been argued that organs should be treated as individual tradable property like other material possessions and assets, on the basis that this would promote individual freedom and increase efficiency in addressing the shortage of organs for transplantation. If organs are to be treated as property, should they be inheritable? This paper seeks to contribute to the idea of organs as inheritable property by providing a defence of a default of the family of a dead person as inheritors of transplantable organs. In the course of discussion, various succession rules for organs and their justifications will be suggested. We then consider two objections to organs as inheritable property. Our intention here is to provoke further thought on whether ownership of one's body parts should be assimilated to property ownership.

  4. Levying Inheritance Tax Now?

    Institute of Scientific and Technical Information of China (English)


    Whether China should levy inheritance tax has become a hot topic of discussion. One survey about levying such a tax on high-income earners conducted by a consultancy agency of China Youth Daily shows 48.46 percent of 11,203 respondents thought it was not yet the right time while 34.03 percent of them said it was and 17.51 percent were not sure. The survey also shows 52.6 percent of the respondents thought affluent Americans’ giving of money to charity was related to inheritance tax.

  5. Inherited Peripheral Neuropathies (United States)

    Saporta, Mario A.; Shy, Michael E.


    SYNOPSIS Charcot Marie Tooth disease (CMT) is a heterogeneous group of inherited peripheral neuropathies in which the neuropathy is the sole or primary component of the disorder, as opposed to diseases in which the neuropathy is part of a more generalized neurological or multisystem syndrome. Due to the great genetic heterogeneity of this condition, it can be challenging for the general neurologist to diagnose patients with specific types of CMT. Here, we review the biology of the inherited peripheral neuropathies, delineate major phenotypic features of the CMT subtypes and suggest strategies for focusing genetic testing. PMID:23642725

  6. Influences of clonality on plant sexual reproduction. (United States)

    Barrett, Spencer C H


    Flowering plants possess an unrivaled diversity of mechanisms for achieving sexual and asexual reproduction, often simultaneously. The commonest type of asexual reproduction is clonal growth (vegetative propagation) in which parental genotypes (genets) produce vegetative modules (ramets) that are capable of independent growth, reproduction, and often dispersal. Clonal growth leads to an expansion in the size of genets and increased fitness because large floral displays increase fertility and opportunities for outcrossing. Moreover, the clonal dispersal of vegetative propagules can assist "mate finding," particularly in aquatic plants. However, there are ecological circumstances in which functional antagonism between sexual and asexual reproductive modes can negatively affect the fitness of clonal plants. Populations of heterostylous and dioecious species have a small number of mating groups (two or three), which should occur at equal frequency in equilibrium populations. Extensive clonal growth and vegetative dispersal can disrupt the functioning of these sexual polymorphisms, resulting in biased morph ratios and populations with a single mating group, with consequences for fertility and mating. In populations in which clonal propagation predominates, mutations reducing fertility may lead to sexual dysfunction and even the loss of sex. Recent evidence suggests that somatic mutations can play a significant role in influencing fitness in clonal plants and may also help explain the occurrence of genetic diversity in sterile clonal populations. Highly polymorphic genetic markers offer outstanding opportunities for gaining novel insights into functional interactions between sexual and clonal reproduction in flowering plants.

  7. Liposomal SLA co-incorporated with PO CpG ODNs or PS CpG ODNs induce the same protection against the murine model of leishmaniasis. (United States)

    Shargh, Vahid Heravi; Jaafari, Mahmoud Reza; Khamesipour, Ali; Jaafari, Iman; Jalali, Seyed Amir; Abbasi, Azam; Badiee, Ali


    First generation Leishmania vaccines consisting of whole killed parasites with or without adjuvants have reached phase 3 trial and failed to show enough efficacy mainly due to the lack of an appropriate adjuvant. In this study, the nuclease-resistant phosphorothioate CpG oligodeoxynucleotides (PS CpG) or nuclease-sensitive phosphodiester CpG ODNs (PO CpG) were used as adjuvants to enhance immunogenicity and rate of protection against leishmaniasis. Due to the susceptibility of PO CpG to nuclease degradation, an efficient liposomal delivery system was developed to protect them from degradation. 1, 2-dioleoyl-3-trimethylammonium-propane (DOTAP) as a cationic lipid was used because of its unique adjuvanticity and electrostatic interaction with negatively charged CpG ODNs. To evaluate the role of liposomal formulation in protection rate and enhanced immune response, BALB/c mice were immunized subcutaneously with liposomal soluble Leishmania antigens (SLA) co-incorporated with PO CpG (Lip-SLA-PO CpG), Lip-SLA-PS CpG, SLA+PO CpG, SLA+PS CpG, SLA or buffer. As criteria for protection, footpad swelling at the site of challenge, parasite loads, the levels of IFN-γ and IL-4, and the IgG subtypes were evaluated. The groups of mice receiving Lip-SLA-PO CpG or Lip-SLA-PS CpG showed a high protection rate compared with the control groups. In addition, there was no significant difference in immune response generation between mice immunized with PS CpG and the group receiving PO CpG when incorporated into the liposomes. The results suggested that liposomal form of PO CpG might be used instead of PS CpG in future vaccine formulations as an efficient adjuvant. Copyright © 2012 Elsevier Ltd. All rights reserved.

  8. Surname Inherited Algorithm Research Based on Artificial Immune System

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    Jing Xie


    Full Text Available To keep the diversity of antibodies in artificial immune system evolution process, this paper puts forward a kind of increase simulation surname inheritance algorithm based on the clonal selection algorithm, and identification and forecast the Vibration Data about CA6140 horizontal  lathe machining slender shaft workpiece prone . The results show that the algorithm has the characteristics of flexible application, strong adaptability, an effective approach to improve efficiency of the algorithm, a good performance of global searching and broad application prospect.

  9. Levying Inheritance Tax Now?

    Institute of Scientific and Technical Information of China (English)


    @@ Whether China should levy inheritance tax has become a hot topic of discussion. One survey about levying such a tax on high-income earners conducted by a consul-tancy agency of China Youth Daily shows 48.46 percent of 11,203 respondents thought it was not yet the right time while 34.03 per-cent of them said it was and 17.51 percent were not sure.

  10. CpG distribution and methylation pattern in porcine parvovirus.

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    Renáta Tóth

    Full Text Available Based on GC content and the observed/expected CpG ratio (oCpGr, we found three major groups among the members of subfamily Parvovirinae: Group I parvoviruses with low GC content and low oCpGr values, Group II with low GC content and high oCpGr values and Group III with high GC content and high oCpGr values. Porcine parvovirus belongs to Group I and it features an ascendant CpG distribution by position in its coding regions similarly to the majority of the parvoviruses. The entire PPV genome remains hypomethylated during the viral lifecycle independently from the tissue of origin. In vitro CpG methylation of the genome has a modest inhibitory effect on PPV replication. The in vitro hypermethylation disappears from the replicating PPV genome suggesting that beside the maintenance DNMT1 the de novo DNMT3a and DNMT3b DNA methyltransferases can't methylate replicating PPV DNA effectively either, despite that the PPV infection does not seem to influence the expression, translation or localization of the DNA methylases. SNP analysis revealed high mutability of the CpG sites in the PPV genome, while introduction of 29 extra CpG sites into the genome has no significant biological effects on PPV replication in vitro. These experiments raise the possibility that beyond natural selection mutational pressure may also significantly contribute to the low level of the CpG sites in the PPV genome.

  11. The evolution of two mutations during clonal expansion. (United States)

    Haeno, Hiroshi; Iwasa, Yoh; Michor, Franziska


    Knudson's two-hit hypothesis proposes that two genetic changes in the RB1 gene are the rate-limiting steps of retinoblastoma. In the inherited form of this childhood eye cancer, only one mutation emerges during somatic cell divisions while in sporadic cases, both alleles of RB1 are inactivated in the growing retina. Sporadic retinoblastoma serves as an example of a situation in which two mutations are accumulated during clonal expansion of a cell population. Other examples include evolution of resistance against anticancer combination therapy and inactivation of both alleles of a metastasis-suppressor gene during tumor growth. In this article, we consider an exponentially growing population of cells that must evolve two mutations to (i) evade treatment, (ii) make a step toward (invasive) cancer, or (iii) display a disease phenotype. We calculate the probability that the population has evolved both mutations before it reaches a certain size. This probability depends on the rates at which the two mutations arise; the growth and death rates of cells carrying none, one, or both mutations; and the size the cell population reaches. Further, we develop a formula for the expected number of cells carrying both mutations when the final population size is reached. Our theory establishes an understanding of the dynamics of two mutations during clonal expansion.

  12. The cognitive principle challenges clonal selection. (United States)

    Cohen, I R


    Here, Irun Cohen argues that the clonal selection paradigm is no longer a convenient paradigm for organizing thinking about the immune system. He contends that most immunologists now investigate questions for which the clonal selection paradigm makes no provision and that one of its major tenets is contradicted by the prevalence of natural autoimmunity. Instead, he proposes a cognitive paradigm.

  13. Clonal integration enhances the performance of a clonal plant species under soil alkalinity stress.

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    Wenjun Zhang

    Full Text Available Clonal plants have been shown to successfully survive in stressful environments, including salinity stress, drought and depleted nutrients through clonal integration between original and subsequent ramets. However, relatively little is known about whether clonal integration can enhance the performance of clonal plants under alkalinity stress. We investigated the effect of clonal integration on the performance of a typical rhizomatous clonal plant, Leymus chinensis, using a factorial experimental design with four levels of alkalinity and two levels of rhizome connection treatments, connected (allowing integration and severed (preventing integration. Clonal integration was estimated by comparing physiological and biomass features between the rhizome-connected and rhizome-severed treatments. We found that rhizome-connected treatment increased the biomass, height and leaf water potential of subsequent ramets at highly alkalinity treatments but did not affect them at low alkalinity treatments. However, rhizome-connected treatment decreased the root biomass of subsequent ramets and did not influence the photosynthetic rates of subsequent ramets. The biomass of original ramets was reduced by rhizome-connected treatment at the highest alkalinity level. These results suggest that clonal integration can increase the performance of clonal plants under alkalinity stress. Rhizome-connected plants showed dramatically increased survival of buds with negative effects on root weight, indicating that clonal integration influenced the resource allocation pattern of clonal plants. A cost-benefit analysis based on biomass measures showed that original and subsequent ramets significantly benefited from clonal integration in highly alkalinity stress, indicating that clonal integration is an important adaptive strategy by which clonal plants could survive in local alkalinity soil.

  14. Clonal evolution in myelodysplastic syndromes (United States)

    da Silva-Coelho, Pedro; Kroeze, Leonie I.; Yoshida, Kenichi; Koorenhof-Scheele, Theresia N.; Knops, Ruth; van de Locht, Louis T.; de Graaf, Aniek O.; Massop, Marion; Sandmann, Sarah; Dugas, Martin; Stevens-Kroef, Marian J.; Cermak, Jaroslav; Shiraishi, Yuichi; Chiba, Kenichi; Tanaka, Hiroko; Miyano, Satoru; de Witte, Theo; Blijlevens, Nicole M. A.; Muus, Petra; Huls, Gerwin; van der Reijden, Bert A.; Ogawa, Seishi; Jansen, Joop H.


    Cancer development is a dynamic process during which the successive accumulation of mutations results in cells with increasingly malignant characteristics. Here, we show the clonal evolution pattern in myelodysplastic syndrome (MDS) patients receiving supportive care, with or without lenalidomide (follow-up 2.5–11 years). Whole-exome and targeted deep sequencing at multiple time points during the disease course reveals that both linear and branched evolutionary patterns occur with and without disease-modifying treatment. The application of disease-modifying therapy may create an evolutionary bottleneck after which more complex MDS, but also unrelated clones of haematopoietic cells, may emerge. In addition, subclones that acquired an additional mutation associated with treatment resistance (TP53) or disease progression (NRAS, KRAS) may be detected months before clinical changes become apparent. Monitoring the genetic landscape during the disease may help to guide treatment decisions. PMID:28429724

  15. Epigenetic Guardian: A Review of the DNA Methyltransferase DNMT3A in Acute Myeloid Leukaemia and Clonal Haematopoiesis (United States)

    Chaudry, Sabah F.


    Acute myeloid leukaemia (AML) is a haematological malignancy characterized by clonal stem cell proliferation and aberrant block in differentiation. Dysfunction of epigenetic modifiers contributes significantly to the pathogenesis of AML. One frequently mutated gene involved in epigenetic modification is DNMT3A (DNA methyltransferase-3-alpha), a DNA methyltransferase that alters gene expression by de novo methylation of cytosine bases at CpG dinucleotides. Approximately 22% of AML and 36% of cytogenetically normal AML cases carry DNMT3A mutations and around 60% of these mutations affect the R882 codon. These mutations have been associated with poor prognosis and adverse survival outcomes for AML patients. Advances in whole-exome sequencing techniques have recently identified a large number of DNMT3A mutations present in clonal cells in normal elderly individuals with no features of haematological malignancy. Categorically distinct from other preleukaemic conditions, this disorder has been termed clonal haematopoiesis of indeterminate potential (CHIP). Further insight into the mutational landscape of CHIP may illustrate the consequence of particular mutations found in DNMT3A and identify specific “founder” mutations responsible for clonal expansion that may contribute to leukaemogenesis. This review will focus on current research and understanding of DNMT3A mutations in both AML and CHIP. PMID:28286768

  16. Modeling the mammalian locomotor CPG: insights from mistakes and perturbations. (United States)

    McCrea, David A; Rybak, Ilya A


    A computational model of the mammalian spinal cord circuitry incorporating a two-level central pattern generator (CPG) with separate half-center rhythm generator (RG) and pattern formation (PF) networks is reviewed. The model consists of interacting populations of interneurons and motoneurons described in the Hodgkin-Huxley style. Locomotor rhythm generation is based on a combination of intrinsic (persistent sodium current dependent) properties of excitatory RG neurons and reciprocal inhibition between the two half-centers comprising the RG. The two-level architecture of the CPG was suggested from an analysis of deletions (spontaneous omissions of activity) and the effects of afferent stimulation on the locomotor pattern and rhythm observed during fictive locomotion in the cat. The RG controls the activity of the PF network that in turn defines the rhythmic pattern of motoneuron activity. The model produces realistic firing patterns of two antagonist motoneuron populations and generates locomotor oscillations encompassing the range of cycle periods and phase durations observed during cat locomotion. A number of features of the real CPG operation can be reproduced with separate RG and PF networks, which would be difficult if not impossible to demonstrate with a classical single-level CPG. The two-level architecture allows the CPG to maintain the phase of locomotor oscillations and cycle timing during deletions and during sensory stimulation. The model provides a basis for functional identification of spinal interneurons involved in generation and control of the locomotor pattern.

  17. Enhanced antibody production in mice to the malaria antigen AMA1 by CPG 7909 requires physical association of CpG and antigen


    Mullen, Gregory E. D.; Aebig, Joan A.; Dobrescu, Gelu; Rausch, Kelly; Lambert, Lynn; Long, Carole A.; Miles, Aaron P.; Saul, Allan


    CpG oligodeoxynucleotides are potent immunostimulants. In this study, CPG 7909 was formulated with the recombinant Plasmodium falciparum protein AMA1-C1 adsorbed to Alhydrogel (aluminum hydroxide) and used to immunize mice. Mice receiving free CPG 7909 in a separate same site injection to the AMA1-C1/Alhydrogel had the same antibody responses as mice receiving AMA1-C1/Alhydrogel alone. For mice immunized with CPG 7909 bound to the AMA1-C1/Alhydrogel formulation, there was a bell shaped CPG 79...

  18. High resolution detection and analysis of CpG dinucleotides methylation using MBD-Seq technology.

    Directory of Open Access Journals (Sweden)

    Xun Lan

    Full Text Available Methyl-CpG binding domain protein sequencing (MBD-seq is widely used to survey DNA methylation patterns. However, the optimal experimental parameters for MBD-seq remain unclear and the data analysis remains challenging. In this study, we generated high depth MBD-seq data in MCF-7 cell and developed a bi-asymmetric-Laplace model (BALM to perform data analysis. We found that optimal efficiency of MBD-seq experiments was achieved by sequencing ∼100 million unique mapped tags from a combination of 500 mM and 1000 mM salt concentration elution in MCF-7 cells. Clonal bisulfite sequencing results showed that the methylation status of each CpG dinucleotides in the tested regions was accurately detected with high resolution using the proposed model. These results demonstrated the combination of MBD-seq and BALM could serve as a useful tool to investigate DNA methylome due to its low cost, high specificity, efficiency and resolution.

  19. CpG 7909: PF 3512676, PF-3512676. (United States)


    CpG 7909 [PF-3512676] is an immunomodulating synthetic oligonucleotide designed to specifically agonise the Toll-like receptor 9 (TLR9). It is being developed for the treatment of cancer [ProMune] as a monotherapy and in combination with chemotherapeutic agents, and it is also under development as an adjuvant [VaxImmune] for vaccines against cancer and infectious diseases. CpG 7909, acting through the TLR9 receptor present in B cells and plasmacytoid dendritic cells, stimulates human B-cell proliferation, enhances antigen-specific antibody production and induces interferon-alpha production, interleukin-10 secretion and natural killer cell activity. Coley Pharmaceutical Group originally developed CpG 7909 using its CpG DNA technology. In March 2005, Coley granted Pfizer an exclusive global license to develop and commercialise CPG 7909 [ProMune] for the treatment, control and prevention of multiple cancer indications. Coley licensed CpG 7909 [VaxImmune] to Chiron Corporation for adjuvant use with Chiron's prophylactic vaccine candidates against infectious diseases in December 2003. Chiron was acquired by and merged into Novartis in April 2006. In 2002, GlaxoSmithKline (GSK) was granted a worldwide, non-exclusive licence to Coley's CpG immunostimulatory oligonucleotides, including CpG 7909 [VaxImmune], for their use as adjuvants for cancer vaccines. In 2000, Coley entered into a co-exclusive licensing agreement with GSK for the development of therapeutic and prophylactic vaccines against infectious diseases. This licensing agreement included CpG 7909 [VaxImmune] and other CpG-based immunostimulatory oligonucleotides. In September 2004, Coley Pharmaceuticals was awarded a 16.9 million US dollars, 5-year contract from the National Institute of Allergy and Infectious Diseases (NIAID), one of the National Institutes of Health (NIH), to support the development of novel immune-activating drugs for defense against bioterror agents. This contract will be used to expand Coley

  20. Enhanced antibody production in mice to the malaria antigen AMA1 by CPG 7909 requires physical association of CpG and antigen. (United States)

    Mullen, Gregory E D; Aebig, Joan A; Dobrescu, Gelu; Rausch, Kelly; Lambert, Lynn; Long, Carole A; Miles, Aaron P; Saul, Allan


    CpG oligodeoxynucleotides are potent immunostimulants. In this study, CPG 7909 was formulated with the recombinant Plasmodium falciparum protein AMA1-C1 adsorbed to Alhydrogel (aluminum hydroxide) and used to immunize mice. Mice receiving free CPG 7909 in a separate same site injection to the AMA1-C1/Alhydrogel had the same antibody responses as mice receiving AMA1-C1/Alhydrogel alone. For mice immunized with CPG 7909 bound to the AMA1-C1/Alhydrogel formulation, there was a bell shaped CPG 7909 dose-response curve with the highest antibody response co-incident with the concentration of CPG 7909 that saturated binding to the Alhydrogel. At a higher CPG 7909 dose where 74% was unbound, there was no enhancement of response over AMA1-C1/Alhydrogel alone. Our results suggest that the adjuvant effects of CpGs are optimal when adsorbed to Alhydrogel and highlight the need for careful characterization of the vaccine formulation.

  1. Dominantly-inherited lop ears. (United States)

    Leung, Alexander K C; Kong, Albert Y F; Robson, W Lane M; McLeod, D Ross


    We describe a four-generation Chinese family that included five members who had an isolated bilateral lop ear anomaly. The presentation suggested a dominant mode of inheritance. The absence of male-to-male transmission does not exclude an X-linked dominant mode of inheritance. Since the phenotypic anomaly of the male proband was no more severe than the affected female members, an autosomal dominant mode of inheritance is most likely. 2007 Wiley-Liss, Inc

  2. A mathematical model of inheritance

    Institute of Scientific and Technical Information of China (English)

    瞿裕忠; 王志坚; 徐家福


    Inheritance is regarded as the hallmark of object-oriented programming languages.A mathematical model of inheritance is presented.In this model,the graph-sorted signature is introduced to represent the algebraic structure of the program,and an extension function on the graph-sorted signatures is used to formally describe the semantics of inheritance.The program’s algebraic structure reflects the syntactic constraints of the language and the corresponding extension function exposes the character of the language’s inheritance.

  3. Inherited autonomic neuropathies. (United States)

    Axelrod, Felicia B; Hilz, Max J


    Inherited autonomic neuropathies are a rare group of disorders associated with sensory dysfunction. As a group they are termed the "hereditary sensory and autonomic neuropathies" (HSAN). Classification of the various autonomic and sensory disorders is ongoing. In addition to the numerical classification of four distinct forms proposed by Dyck and Ohta (1975), additional entities have been described. The best known and most intensively studied of the HSANs are familial dysautonomia (Riley-Day syndrome or HSAN type III) and congenital insensitivity to pain with anhidrosis (HSAN type IV). Diagnosis of the HSANs depends primarily on clinical examinations and specific sensory and autonomic assessments. Pathologic examinations are helpful in confirming the diagnosis and in differentiating between the different disorders. In recent years identification of specific genetic mutations for some disorders has aided diagnosis. Replacement or definitive therapies are not available for any of the disorders so that treatment remains supportive and directed toward specific symptoms.

  4. Inherited mitochondrial optic neuropathies (United States)

    Yu-Wai-Man, P; Griffiths, P G; Hudson, G; Chinnery, P F


    Leber hereditary optic neuropathy (LHON) and autosomal dominant optic atrophy (DOA) are the two most common inherited optic neuropathies and they result in significant visual morbidity among young adults. Both disorders are the result of mitochondrial dysfunction: LHON from primary mitochondrial DNA (mtDNA) mutations affecting the respiratory chain complexes; and the majority of DOA families have mutations in the OPA1 gene, which codes for an inner mitochondrial membrane protein critical for mtDNA maintenance and oxidative phosphorylation. Additional genetic and environmental factors modulate the penetrance of LHON, and the same is likely to be the case for DOA which has a markedly variable clinical phenotype. The selective vulnerability of retinal ganglion cells (RGCs) is a key pathological feature and understanding the fundamental mechanisms that underlie RGC loss in these disorders is a prerequisite for the development of effective therapeutic strategies which are currently limited. PMID:19001017

  5. Porphyromonas gingivalis: a clonal pathogen?

    Directory of Open Access Journals (Sweden)

    Morten Enersen


    Full Text Available The introduction of multilocus sequence typing (MLST in infectious disease research has allowed standardized typing of bacterial clones. Through multiple markers around the genome, it is possible to determine the sequence type (ST of bacterial isolates to establish the population structure of a species. For the periodontal pathogen, Porphyromonas gingivalis, the MLST scheme has been established at, and data from the database indicate a high degree of genetic diversity and a weakly clonal population structure comparable with Neisseria menigitidis. The major fimbriae (FimA have been held responsible for the adhesive properties of P. gingivalis and represent an important virulence factor. The fimA genotyping method (PCR based indicate that fimA genotype II, IV and Ib are associated with diseased sites in periodontitis and tissue specimens from cardiovascular disease. fimA genotyping of the isolates in the MLST database supports the association of genotypes II and IV with periodontitis. As a result of multiple positive PCR reactions in the fimA genotyping, sequencing of the fimA gene revealed only minor nucleotide variation between isolates of the same and different genotypes, suggesting that the method should be redesigned or re-evaluated. Results from several investigations indicate a higher intraindividual heterogeneity of P. gingivalis than found earlier. Detection of multiple STs from one site in several patients with “refractory” periodontitis, showed allelic variation in two housekeeping genes indicating recombination between different clones within the periodontal pocket.

  6. CpG oligodeoxyribonucleotides protect mice from Burholderia pseudomallei but not Francisella tularensis Schu 54 aersols (United States)


    CpG ODN 10103 performs comparably in mice to CpG ODN 7909 (5’-TCGTCGTTTTGTCGTTTTGTCGTT-3’), which was previously reported to protect the BALB/c mice...SHORT REPORT Open Access CpG oligodeoxyribonucleotides protect mice from Burkholderia pseudomallei but not Francisella tularensis Schu S4 aerosols...that CpG oligodeoxyribonucleotides (ODN) protect mice from various bacterial pathogens, including Burkholderia pseudomallei and Francisella tularensis

  7. Inherited epidermolysis bullosa

    Directory of Open Access Journals (Sweden)

    Fine Jo-David


    Full Text Available Abstract Inherited epidermolysis bullosa (EB encompasses a number of disorders characterized by recurrent blister formation as the result of structural fragility within the skin and selected other tissues. All types and subtypes of EB are rare; the overall incidence and prevalence of the disease within the United States is approximately 19 per one million live births and 8 per one million population, respectively. Clinical manifestations range widely, from localized blistering of the hands and feet to generalized blistering of the skin and oral cavity, and injury to many internal organs. Each EB subtype is known to arise from mutations within the genes encoding for several different proteins, each of which is intimately involved in the maintenance of keratinocyte structural stability or adhesion of the keratinocyte to the underlying dermis. EB is best diagnosed and subclassified by the collective findings obtained via detailed personal and family history, in concert with the results of immunofluorescence antigenic mapping, transmission electron microscopy, and in some cases, by DNA analysis. Optimal patient management requires a multidisciplinary approach, and revolves around the protection of susceptible tissues against trauma, use of sophisticated wound care dressings, aggressive nutritional support, and early medical or surgical interventions to correct whenever possible the extracutaneous complications. Prognosis varies considerably and is based on both EB subtype and the overall health of the patient.

  8. Inherited thrombophilia and pregnancy complications

    NARCIS (Netherlands)

    de Jong, P.G.


    The research presented in this thesis addresses several aspects of the association between inherited thrombophilia and pregnancy complications. Antithrombotic therapy is prescribed to women with recurrent miscarriage and antiphospholipid syndrome to increase their chance of live birth in a subsequen

  9. Inherited thrombophilia and pregnancy complications

    NARCIS (Netherlands)

    de Jong, P.G.


    The research presented in this thesis addresses several aspects of the association between inherited thrombophilia and pregnancy complications. Antithrombotic therapy is prescribed to women with recurrent miscarriage and antiphospholipid syndrome to increase their chance of live birth in a

  10. Effect of amino groups of mesoporous silica nanoparticles on CpG oligodexynucleotide delivery (United States)

    Xu, Yi; Claiden, Peter; Zhu, Yufang; Morita, Hiromi; Hanagata, Nobutaka


    In this study, we proposed to modify mesoporous silica nanoparticles (MSNs) with 3-aminopropyltriethoxysilane (NH2-TES), aminoethylaminopropyltriethoxysilane (2NH2-TES) and 3-[2-(2-aminoethylamino)ethylamino] propyl-trimethoxysilane (3NH2-TES) for binding of cytosine-phosphate-guanosine oligodexynucleotides (CpG ODN), and investigated the effect of different amino groups of MSNs on the CpG ODN delivery. Serum stability, in vitro cytotoxicity, and cytokine interleukin-6 (IL-6) induction by MSN-NH2/CpG, MSN-2NH2/CpG and MSN-3NH2/CpG complexes were investigated in detail. The results showed that three kinds of aminated-MSN-based CpG ODN delivery systems had no cytotoxicity to RAW264.7 cells, and binding of CpG ODN to MSN-NH2, MSN-2NH2 and MSN-3NH2 nanoparticles enhanced the serum stability of CpG ODN due to protection by the nanoparticles. However, three aminated MSN-based CpG ODN delivery systems exhibited different CpG ODN delivery efficiency, and MSN-NH2/CpG complexes had the highest ability to induce IL-6 secretion.

  11. Phenotypic plasticity and specialization in clonal versus non-clonal plants: A data synthesis (United States)

    Fazlioglu, Fatih; Bonser, Stephen P.


    Reproductive strategies can be associated with ecological specialization and generalization. Clonal plants produce lineages adapted to the maternal habitat that can lead to specialization. However, clonal plants frequently display high phenotypic plasticity (e.g. clonal foraging for resources), factors linked to ecological generalization. Alternately, sexual reproduction can be associated with generalization via increasing genetic variation or specialization through rapid adaptive evolution. Moreover, specializing to high or low quality habitats can determine how phenotypic plasticity is expressed in plants. The specialization hypothesis predicts that specialization to good environments results in high performance trait plasticity and specialization to bad environments results in low performance trait plasticity. The interplay between reproductive strategies, phenotypic plasticity, and ecological specialization is important for understanding how plants adapt to variable environments. However, we currently have a poor understanding of these relationships. In this study, we addressed following questions: 1) Is there a relationship between phenotypic plasticity, specialization, and reproductive strategies in plants? 2) Do good habitat specialists express greater performance trait plasticity than bad habitat specialists? We searched the literature for studies examining plasticity for performance traits and functional traits in clonal and non-clonal plant species from different habitat types. We found that non-clonal (obligate sexual) plants expressed greater performance trait plasticity and functional trait plasticity than clonal plants. That is, non-clonal plants exhibited a specialist strategy where they perform well only in a limited range of habitats. Clonal plants expressed less performance loss across habitats and a more generalist strategy. In addition, specialization to good habitats did not result in greater performance trait plasticity. This result was

  12. Structure-dependent immunostimulatory effect of CpG oligodeoxynucleotides and their delivery system

    Directory of Open Access Journals (Sweden)

    Hanagata N


    Full Text Available Nobutaka HanagataNanotechnology Innovation Station, National Institute for Materials Science, Tsukuba, Ibaraki, and Graduate School of Life Science, Hokkaido University, Kita-ku, Sapporo, JapanAbstract: Unmethylated cytosine-phosphate-guanosine (CpG oligodeoxynucleotides (ODNs are recognized by Toll-like receptor 9 (TLR9 found in antigen-presenting cells and B cells and can activate the immune system. Using CpG ODNs as an adjuvant has been found to be effective for treating infectious diseases, cancers, and allergies. Because natural ODNs with only a phosphodiester backbone are easily degraded by nuclease (deoxyribonuclease [DNase] in serum, CpG ODNs with a phosphorothioate backbone have been studied for clinical application. CpG ODNs with a phosphorothioate backbone have raised concern regarding undesirable side effects; however, several CpG ODNs with only a phosphodiester backbone have been reported to be stable in serum and to show an immunostimulatory effect. In recent years, research has been conducted on delivery systems for CpG ODNs using nanoparticles (NPs. The advantages of NP-based delivery of CpG ODN include (1 it can protect CpG ODN from DNase, (2 it can retain CpG ODN inside the body for a long period of time, (3 it can improve the cellular uptake efficiency of CpG ODN, and (4 it can deliver CpG ODN to the target tissues. Because the target cells of CpG ODN are cells of the immune system and TLR9, the receptor of CpG ODN is localized in endolysosomes, CpG ODN delivery systems are required to have qualities different from other nucleic acid drugs such as antisense DNA and small interfering RNA. Studies until now have reported various NPs as carriers for CpG ODN delivery. This review presents DNase-resistant CpG ODNs with various structures and their immunostimulatory effects and also focuses on delivery systems of CpG ODNs that utilize NPs. Because CpG ODNs interact with TLR9 and activate both the innate and the adaptive immune

  13. CPG Control for Biped Hopping Robot in Unpredictable Environment

    Institute of Scientific and Technical Information of China (English)

    Tingting Wang; Wei Guo; Mantian Li; Fusheng Zha; Lining Sun


    A CPG control mechanism is proposed for hopping motion control of biped robot in unpredictable environment.Based on analysis of robot motion and biological observation of animal's control mechanism,the motion control task is divided into two simple parts:motion sequence control and output force control.Inspired by a two-level CPG model,a two-level CPG control mechanism is constructed to coordinate the drivers of robot joint,while various feedback information are introduced into the control mechanism.Interneurons within the control mechanism are modeled to generate motion rhythm and pattern promptly for motion sequence control; motoneurons are modeled to control output forces of joint drivers in real time according to feedbacks.The control system can perceive changes caused by unknown perturbations and environment changes according to feedback information,and adapt to unpredictable environment by adjusting outputs of neurons.The control mechanism is applied to a biped hopping robot in unpredictable environment on simulation platform,and stable adaptive motions are obtained.

  14. Electrophysiological Representation of Scratching CPG Activity in the Cerebellum (United States)

    Martínez-Silva, Lourdes; Manjarrez, Elias; Gutiérrez-Ospina, Gabriel; Quevedo, Jorge N.


    We analyzed the electrical activity of neuronal populations in the cerebellum and the lumbar spinal cord during fictive scratching in adult decerebrate cats before and after selective sections of the Spino-Reticulo Cerebellar Pathway (SRCP) and the Ventral-Spino Cerebellar Tract (VSCT). During fictive scratching, we found a conspicuous sinusoidal electrical activity, called Sinusoidal Cerebellar Potentials (SCPs), in the cerebellar vermis, which exhibited smaller amplitude in the paravermal and hemisphere cortices. There was also a significant spino-cerebellar coherence between these SCPs and the lumbar sinusoidal cord dorsum potentials (SCDPs). However, during spontaneous activity such spino-cerebellar coherence between spontaneous potentials recorded in the same regions decreased. We found that the section of the SRCP and the VSCT did not abolish the amplitude of the SCPs, suggesting that there are additional pathways conveying information from the spinal CPG to the cerebellum. This is the first evidence that the sinusoidal activity associated to the spinal CPG circuitry for scratching has a broad representation in the cerebellum beyond the sensory representation from hindlimbs previously described. Furthermore, the SCPs represent the global electrical activity of the spinal CPG for scratching in the cerebellar cortex. PMID:25350378

  15. Evolutionary perspectives on clonal reproduction in vertebrate animals. (United States)

    Avise, John C


    A synopsis is provided of different expressions of whole-animal vertebrate clonality (asexual organismal-level reproduction), both in the laboratory and in nature. For vertebrate taxa, such clonal phenomena include the following: human-mediated cloning via artificial nuclear transfer; intergenerational clonality in nature via parthenogenesis and gynogenesis; intergenerational hemiclonality via hybridogenesis and kleptogenesis; intragenerational clonality via polyembryony; and what in effect qualifies as clonal replication via self-fertilization and intense inbreeding by simultaneous hermaphrodites. Each of these clonal or quasi-clonal mechanisms is described, and its evolutionary genetic ramifications are addressed. By affording an atypical vantage on standard vertebrate reproduction, clonality offers fresh perspectives on the evolutionary and ecological significance of recombination-derived genetic variety.

  16. PCR clonality detection in Hodgkin lymphoma.

    NARCIS (Netherlands)

    Hebeda, K.M.; Altena, M.C. van; Rombout, P.D.M.; Krieken, J.H.J.M. van; Groenen, P.J.T.A.


    B-cell clonality detection in whole tissue is considered indicative of B-cell non-Hodgkin lymphoma (NHL). We tested frozen tissue of 24 classical Hodgkin lymphomas (cHL) with a varying tumor cell load with the multiplex polymerase chain reaction (PCR) primer sets for IGH and IGK gene rearrangement (

  17. HIV genetic information and clonal growth (United States)

    Based on an analysis of blood cells from five HIV-infected individuals, NCI researchers have identified more than 2,400 HIV DNA insertion sites. Analysis of these sites showed that there is extensive clonal expansion (growth) of HIV infected cells.

  18. The impact of clonality on parasite population genetic structure

    Directory of Open Access Journals (Sweden)

    Prugnolle F.


    Full Text Available In this paper, we briefly review the consequences of clonal reproduction on the apportionment of genetic diversity in parasite populations. We distinguish three kinds of parasite life-cycle where clonal reproduction occurs. The consequences of this mode of reproduction for the different kinds of parasite life-cycles are described. We here particularly focus on clonal diploids.

  19. Clonal hematopoiesis in acquired aplastic anemia (United States)


    Clonal hematopoiesis (CH) in aplastic anemia (AA) has been closely linked to the evolution of late clonal disorders, including paroxysmal nocturnal hemoglobinuria and myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML), which are common complications after successful immunosuppressive therapy (IST). With the advent of high-throughput sequencing of recent years, the molecular aspect of CH in AA has been clarified by comprehensive detection of somatic mutations that drive clonal evolution. Genetic abnormalities are found in ∼50% of patients with AA and, except for PIGA mutations and copy-neutral loss-of-heterozygosity, or uniparental disomy (UPD) in 6p (6pUPD), are most frequently represented by mutations involving genes commonly mutated in myeloid malignancies, including DNMT3A, ASXL1, and BCOR/BCORL1. Mutations exhibit distinct chronological profiles and clinical impacts. BCOR/BCORL1 and PIGA mutations tend to disappear or show stable clone size and predict a better response to IST and a significantly better clinical outcome compared with mutations in DNMT3A, ASXL1, and other genes, which are likely to increase their clone size, are associated with a faster progression to MDS/AML, and predict an unfavorable survival. High frequency of 6pUPD and overrepresentation of PIGA and BCOR/BCORL1 mutations are unique to AA, suggesting the role of autoimmunity in clonal selection. By contrast, DNMT3A and ASXL1 mutations, also commonly seen in CH in the general population, indicate a close link to CH in the aged bone marrow, in terms of the mechanism for selection. Detection and close monitoring of somatic mutations/evolution may help with prediction and diagnosis of clonal evolution of MDS/AML and better management of patients with AA. PMID:27121470

  20. From Neo-Darwinism to Epigenetic Inheritance


    Axholm, Ida; Ranum, Kasper; Al-Makdisi Razeeghi, Redaa


    Transgenerational epigenetic inheritance is at variance with the neo-Darwinian theory of inheritance, and this possibly has important implications for how we view evolution, since it could allow for a kind of inheritance of acquired characteristics. We have applied Imre Lakatos and Thomas Kuhn’s models of scientific change and investigated if they can accurately describe the change in the view on inheritance from neo-Darwinism to a view that includes transgenerational epigenetic inheritance, ...

  1. Mechanisms of inherited cancer susceptibility

    Institute of Scientific and Technical Information of China (English)

    Shirley HODGSON


    A small proportion of many cancers are due to inherited mutations in genes, which result in a high risk to the individual of developing specific cancers. There are several classes of genes that may be involved: tumour suppressor genes, oncogenes, genes encoding proteins involved in DNA repair and cell cycle control, and genes involved in stimulating the angiogenic pathway. Alterations in susceptibility to cancer may also be due to variations in genes involved in carcinogen metabolism. This review discusses examples of some of these genes and the associated clinical conditions caused by the inheritance of mutations in such genes.

  2. The inheritance of groin hernia

    DEFF Research Database (Denmark)

    Burcharth, J; Pommergaard, H C; Rosenberg, Jacob


    Groin hernia has been proposed to be hereditary; however, a clear hereditary pattern has not been established yet. The purpose of this review was to analyze studies evaluating family history and inheritance patterns and to investigate the possible heredity of groin hernias.......Groin hernia has been proposed to be hereditary; however, a clear hereditary pattern has not been established yet. The purpose of this review was to analyze studies evaluating family history and inheritance patterns and to investigate the possible heredity of groin hernias....

  3. Inherited ataxia with slow saccades

    Directory of Open Access Journals (Sweden)

    R T Chakor


    Full Text Available Ataxia is a symptom of cerebellar dysfunction. Slowly progressive ataxia, dysarthria in an adult with a positive family history suggests an inherited cerebellar ataxia. We present an adult with gradually progressive ataxia and slow saccades. There was history of similar illness in his son. Genetic testing for spinocerebellar ataxia 2 was positive. We discuss the various inherited ataxias, causes of acute, progressive ataxia syndromes, episodic ataxias and ataxia associated with other neurological signs like peripheral neuropathy, pyramidal features, movement disorders and cognitive decline.

  4. Improved detection of chromosomal abnormalities in chronic lymphocytic leukemia by conventional cytogenetics using CpG oligonucleotide and interleukin-2 stimulation: A Belgian multicentric study. (United States)

    Put, Natalie; Konings, Peter; Rack, Katrina; Jamar, Mauricette; Van Roy, Nadine; Libouton, Jeanne-Marie; Vannuffel, Pascal; Sartenaer, Daniel; Ameye, Geneviève; Speleman, Frank; Herens, Christian; Poirel, Hélène A; Moreau, Yves; Hagemeijer, Anne; Vandenberghe, Peter; Michaux, Lucienne


    We performed a multicentric study to assess the impact of two different culture procedures on the detection of chromosomal abnormalities in 217 consecutive unselected cases with chronic lymphocytic leukemia (CLL) referred for routine analysis either at the time of diagnosis (n = 172) or during disease evolution (n = 45). Parallel cultures of peripheral blood or bone marrow were set up with the addition of either the conventional B-cell mitogen 12-O-tetradecanoyl-phorbol-13-acetate (TPA) or a combination of CpG oligonucleotide (CpG) and interleukin-2 (IL-2). Cytogenetic analyses were performed on both cultures. Clonal abnormalities were identified in 116 cases (53%). In 78 cases (36%), the aberrant clone was detected in both cultures. Among these, the percentages of aberrant metaphases were similar in both conditions in 17 cases, higher in the CpG/IL-2 culture in 43 cases, and higher in the TPA culture in 18 cases. Clonal aberrations were detected in only one culture, either in CpG/IL-2 or TPA in 33 (15%) and 5 (2%) cases, respectively. Taken together, abnormal karyotypes were observed in 51% with CpG/IL-2 and 38% with TPA (P cytogenetic analysis in 80 cases: del(13q) (n = 71), del(11q) (n = 5), +12 (n = 2), del(14q) (n = 1), and del(17p) (n = 1). In conclusion, our results confirm that CpG/IL-2 stimulation increases the detection rate of chromosomal abnormalities in CLL compared with TPA and that further improvement can be obtained by FISH. However, neither conventional cytogenetics nor FISH detected all aberrations, demonstrating the complementary nature of these techniques.

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

    Directory of Open Access Journals (Sweden)

    Mohita Upadhyay

    Full Text Available 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

  6. Enhancement of the Anthrax AVA Vaccine with CpG ODN’s (United States)


    NUMBER OF PAGES 20. LIMITATION OF ABSTRACT UL - 28-Aug-2005 Final Report on ACCELERATE ANTHRAX: CpG 7909 Vaccine Adjuvant Program Report Title...Vaccine Adsorbed (BioThrax?) Combined with CPG 7909 in Normal Volunteers” was completed and presented at the 2005 Interscience Conference on Antimicrobial...Agents and Chemotherapy in a poster entitled “Marked Enhancement Of Antibody Response To Anthrax Vaccine Adsorbed With CPG 7909 In Healthy

  7. Inherited or acquired metabolic disorders. (United States)

    Eichler, Florian; Ratai, Eva; Carroll, Jason J; Masdeu, Joseph C


    This chapter starts with a description of imaging of inherited metabolic disorders, followed by a discussion on imaging of acquired toxic-metabolic disorders of the adult brain. Neuroimaging is crucial for the diagnosis and management of a number of inherited metabolic disorders. Among these, inherited white-matter disorders commonly affect both the nervous system and endocrine organs. Magnetic resonance imaging (MRI) has enabled new classifications of these disorders that have greatly enhanced both our diagnostic ability and our understanding of these complex disorders. Beyond the classic leukodystrophies, we are increasingly recognizing new hereditary leukoencephalopathies such as the hypomyelinating disorders. Conventional imaging can be unrevealing in some metabolic disorders, but proton magnetic resonance spectroscopy (MRS) may be able to directly visualize the metabolic abnormality in certain disorders. Hence, neuroimaging can enhance our understanding of pathogenesis, even in the absence of a pathologic specimen. This review aims to present pathognomonic brain MRI lesion patterns, the diagnostic capacity of proton MRS, and information from clinical and laboratory testing that can aid diagnosis. We demonstrate that applying an advanced neuroimaging approach enhances current diagnostics and management. Additional information on inherited and metabolic disorders of the brain can be found in Chapter 63 in the second volume of this series.

  8. Transgenerational epigenetic inheritance in plants. (United States)

    Hauser, Marie-Theres; Aufsatz, Werner; Jonak, Claudia; Luschnig, Christian


    Interest in transgenerational epigenetic inheritance has intensified with the boosting of knowledge on epigenetic mechanisms regulating gene expression during development and in response to internal and external signals such as biotic and abiotic stresses. Starting with an historical background of scantily documented anecdotes and their consequences, we recapitulate the information gathered during the last 60 years on naturally occurring and induced epialleles and paramutations in plants. We present the major players of epigenetic regulation and their importance in controlling stress responses. The effect of diverse stressors on the epigenetic status and its transgenerational inheritance is summarized from a mechanistic viewpoint. The consequences of transgenerational epigenetic inheritance are presented, focusing on the knowledge about its stability, and in relation to genetically fixed mutations, recombination, and genomic rearrangement. We conclude with an outlook on the importance of transgenerational inheritance for adaptation to changing environments and for practical applications. This article is part of a Special Issue entitled "Epigenetic control of cellular and developmental processes in plants".

  9. Inherited myopathies and muscular dystrophies

    NARCIS (Netherlands)

    Cardamone, Michael; Darras, Basil T.; Ryan, Monique M.

    The inherited myopathies and muscular dystrophies are a diverse group of muscle diseases presenting with common complaints and physical signs: weakness, motor delay, and respiratory and bulbar dysfunction. The myopathies are caused by genetic defects in the contractile apparatus of muscle, and

  10. CpG + CpNpG Analysis of Protein-Coding Sequences from Tomato

    DEFF Research Database (Denmark)

    Hobolth, Asger; Nielsen, Rasmus; Wang, Ying


    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....

  11. Consolidated Recovered Materials Advisory Notice (RMAN) for the Comprehensive Procurement Guideline (CPG) (United States)

    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...

  12. Drug hypersensitivity in clonal mast cell disorders

    DEFF Research Database (Denmark)

    Bonadonna, P; Pagani, M; Aberer, W


    tryptase determination, physical examination for cutaneous mastocytosis lesions, and clinical characteristics of anaphylactic reaction might be useful for differential diagnosis. In this position paper, the ENDA group performed a literature search on immediate drug hypersensitivity reactions in clonal MC...... disorders using MEDLINE, EMBASE, and Cochrane Library, reviewed and evaluated the literature in five languages using the GRADE system for quality of evidence and strength of recommendation....

  13. Distinguishing between incomplete lineage sorting and genomic introgressions: complete fixation of allospecific mitochondrial DNA in a sexually reproducing fish (Cobitis; Teleostei, despite clonal reproduction of hybrids.

    Directory of Open Access Journals (Sweden)

    Lukas Choleva

    Full Text Available Distinguishing between hybrid introgression and incomplete lineage sorting causing incongruence among gene trees in that they exhibit topological differences requires application of statistical approaches that are based on biologically relevant models. Such study is especially challenging in hybrid systems, where usual vectors mediating interspecific gene transfers--hybrids with Mendelian heredity--are absent or unknown. Here we study a complex of hybridizing species, which are known to produce clonal hybrids, to discover how one of the species, Cobitis tanaitica, has achieved a pattern of mito-nuclear mosaic genome over the whole geographic range. We appplied three distinct methods, including the method using solely the information on gene tree topologies, and found that the contrasting mito-nuclear signal might not have resulted from the retention of ancestral polymorphism. Instead, we found two signs of hybridization events related to C. tanaitica; one concerning nuclear gene flow and the other suggested mitochondrial capture. Interestingly, clonal inheritance (gynogenesis of contemporary hybrids prevents genomic introgressions and non-clonal hybrids are either absent or too rare to be detected among European Cobitis. Our analyses therefore suggest that introgressive hybridizations are rather old episodes, mediated by previously existing hybrids whose inheritance was not entirely clonal. Cobitis complex thus supports the view that the type of resulting hybrids depends on a level of genomic divergence between sexual species.

  14. Inheriting geodesic flows

    Indian Academy of Sciences (India)

    D B Lortan; S D Maharaj; N K Dadhich


    We investigate the propagation equations for the expansion, vorticity and shear for perfect fluid space-times which are geodesic. It is assumed that space-time admits a conformal Killing vector which is inheriting so that fluid flow lines are mapped conformally. Simple constraints on the electric and magnetic parts of the Weyl tensor are found for conformal symmetry. For homothetic vectors the vorticity and shear are free; they vanish for nonhomothetic vectors. We prove a conjecture for conformal symmetries in the special case of inheriting geodesic flows: there exist no proper conformal Killing vectors ( ≠ 0) for perfect fluids except for Robertson–Walker space-times. For a nonhomothetic vector field the propagation of the quantity ln () along the integral curves of the symmetry vector is homogeneous.

  15. CZ: Multiple Inheritance Without Diamonds (United States)


    be solved by allowing renaming (e.g., Eiffel [24]) or by linearizing the class hierarchy [33, 32]. However, there is still no satisfactory solution to...desirable semantics; it is supported in languages such as Scala, Eiffel , and C++ (the last through virtual inheritance) [28, 24, 18]. Next, diamond...Languages that attempt to solve the object initialization problem include Eiffel [24], C++ [18], Scala [28] and Smalltalk with stateful traits [8

  16. Epigenetic Inheritance Across the Landscape

    Directory of Open Access Journals (Sweden)

    Amy Vaughn Whipple


    Full Text Available The study of epigenomic variation at the landscape-level in plants may add important insight to studies of adaptive variation. A major goal of landscape genomic studies is to identify genomic regions contributing to adaptive variation across the landscape. Heritable variation in epigenetic marks, resulting in transgenerational plasticity, can influence fitness-related traits. Epigenetic marks are influenced by the genome, the environment, and their interaction, and can be inherited independently of the genome. Thus, epigenomic variation likely influences the heritability of many adaptive traits, but the extent of this influence remains largely unknown. Here we summarize the relevance of epigenetic inheritance to ecological and evolutionary processes, and review the literature on landscape-level patterns of epigenetic variation. Landscape-level patterns of epigenomic variation in plants generally show greater levels of isolation by distance and isolation by environment then is found for the genome, but the causes of these patterns are not yet clear. Linkage between the environment and epigenomic variation has been clearly shown within a single generation, but demonstrating transgenerational inheritance requires more complex breeding and/or experimental designs. Transgenerational epigenetic variation may alter the interpretation of landscape genomic studies that rely upon phenotypic analyses, but should have less influence on landscape genomic approaches that rely upon outlier analyses or genome-environment associations. We suggest that multi-generation common garden experiments conducted across multiple environments will allow researchers to understand which parts of the epigenome are inherited, as well as to parse out the relative contribution of heritable epigenetic variation to the phenotype.

  17. Utilizing inheritance in requirements engineering (United States)

    Kaindl, Hermann


    The scope of this paper is the utilization of inheritance for requirements specification, i.e., the tasks of analyzing and modeling the domain, as well as forming and defining requirements. Our approach and the tool supporting it are named RETH (Requirements Engineering Through Hypertext). Actually, RETH uses a combination of various technologies, including object-oriented approaches and artificial intelligence (in particular frames). We do not attempt to exclude or replace formal representations, but try to complement and provide means for gradually developing them. Among others, RETH has been applied in the CERN (Conseil Europeen pour la Rechereche Nucleaire) Cortex project. While it would be impossible to explain this project in detail here, it should be sufficient to know that it deals with a generic distributed control system. Since this project is not finished yet, it is difficult to state its size precisely. In order to give an idea, its final goal is to substitute the many existing similar control systems at CERN by this generic approach. Currently, RETH is also tested using real-world requirements for the Pastel Mission Planning System at ESOC in Darmstadt. First, we outline how hypertext is integrated into a frame system in our approach. Moreover, the usefulness of inheritance is demonstrated as performed by the tool RETH. We then summarize our experiences of utilizing inheritance in the Cortex project. Lastly, RETH will be related to existing work.

  18. Epigenetic inheritance, prions and evolution

    Indian Academy of Sciences (India)



    The field of epigenetics has grown explosively in the past two decades or so. As currently defined, epigenetics deals with heritable, metastable and usually reversible changes that do not involve alterations in DNA sequence, but alter the way that information encoded inDNAis utilized.The bulk of current research in epigenetics concerns itself with mitotically inherited epigenetic processes underlying development or responses to environmental cues (as well as the role of mis-regulation or dys-regulation of such processes in disease and ageing), i.e., epigenetic changes occurring within individuals. However, a steadily growing body of evidence indicates that epigenetic changes may also sometimes be transmitted from parents to progeny, meiotically in sexually reproducingorganisms or mitotically in asexually reproducing ones. Such transgenerational epigenetic inheritance (TEI) raises obvious questions about a possible evolutionary role for epigenetic ‘Lamarckian’ mechanisms in evolution, particularly when epigenetic modifications are induced by environmental cues. In this review I attempt a brief overview of the periodically reviewed and debated ‘classical’ TEI phenomena and their possible implications for evolution. The review then focusses on a less-discussed, unique kind of protein-onlyepigenetic inheritance mediated by prions. Much remains to be learnt about the mechanisms, persistence and effects of TEI. The jury is still out on their evolutionary significance and how these phenomena should be incorporated into evolutionary theory, but the growing weight of evidence indicates that likely evolutionary roles for these processes need to be seriously explored.

  19. Suppression of HIV replication in vitro by CpG and CpG conjugated to the non toxic B subunit of cholera toxin. (United States)

    Nowroozalizadeh, Salma; Jansson, Marianne; Adamsson, Jenni; Lindblad, Marianne; Fenyö, Eva-Maria; Holmgren, Jan; Harandi, Ali M


    Administration of oligodeoxynucleotides (ODNs) containing CpG motifs generates a rapid and potent response of CC-chemokines, known as ligands of the HIV-1 co-receptor CCR5, in the murine female genital tract. The present study explored the potential HIV inhibitory activities of different human CpG prototypes either alone or conjugated to the non-toxic subunit of cholera toxin (CTB). Results showed that in vitro replication of both HIV-1 and HIV-2 can be suppressed by different human CpG prototypes. Importantly, the conjugation of CpG ODN to CTB (CTB-CpG) enhanced the antiviral activity of CpG against primary HIV-1 isolates of both R5 and X4 phenotypes in peripheral blood mononuclear cells (PBMC) as well as U87.CD4 co-receptor indicator cells. CTB-CpGs triggered higher amounts of MIP-1alpha, and MIP-1beta in PBMC than the corresponding CpG ODNs, which may explain the superior antiviral effect of CTB-CpG against R5 virus in PBMC. Incubation of PBMC with CpG ODN and CTB-CpG did not alter surface expression of HIV-1 receptors indicating that the observed anti-HIV-1 effect is not mediated through down regulation of HIV-1 receptors on target cells. Further, the enhanced antiviral effect of CTB-CpG was dependent on the presence of phosphorothioate backbone in the ODN, whereas the presence of CpG motif in ODNs was dispensable. These results have implications for the development of novel intervention strategies to prevent HIV infection.

  20. CpG dinucleotide frequencies reveal the role of host methylation capabilities in parvovirus evolution. (United States)

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


    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.

  1. Effects of systemic pretreatment with CpG oligodeoxynucleotides on skin wound healing in mice. (United States)

    Hergert, Bettina; Grambow, Eberhard; Butschkau, Antje; Vollmar, Brigitte


    Unmethylated CpG oligodeoxynucleotides (ODN) bind to the Toll-like receptor 9, thus stimulating the immune system. To study the effects of systemic pretreatment with CpG ODN on dermal regeneration, C57BL6/J Tyr mice were treated with CpG or control ODN 6 days prior to implantation of a dorsal skinfold chamber and skin wounding. Wound epithelialization was analyzed by planimetric microscopy. On day 18, wound tissues were taken for (immuno)histochemical staining. CpG ODN increased epithelialization compared with control ODN treatment. Histological analysis revealed reduced capillary density, reduced wound cellularity, and reduced numbers of infiltrating leukocytes, as well as reduced F4/80-positive macrophages, but increased numbers of RELM-α-positive M2 macrophages after CpG ODN treatment, reflecting a better quality of wound healing on day 18 compared with control ODN treatment. Reverse transcription-polymerase chain reaction analysis of Toll-like receptor 9 showed the receptor expression on both fibroblasts and keratinocytes. Fibroblasts showed an increase of migration upon increasing dosages of CpG and not control ODN, reaching ∼50% of the response of basic fibroblast growth factor-exposed cells. Keratinocytes dose-dependently responded to both CpG and control ODN up to values found in keratinocyte growth factor-exposed cells. In summary, CpG ODN support late tissue-remodeling processes that contribute to resolution of inflammation and solid wounds during skin regeneration.

  2. Modulation of CpG oligodeoxynucleotide-mediated immune stimulation by locked nucleic acid (LNA)

    DEFF Research Database (Denmark)

    Vollmer, Jörg; Jepsen, Jan Stenvang; Uhlmann, Eugen


    Locked nucleic acid (LNA) is an RNA derivative that when introduced into oligodeoxynucleotides (ODN), mediates high efficacy and stability. CpG ODNs are potent immune stimulators and are recognized by toll-like receptor-9 (TLR9). Some phosphorothioate antisense ODNs bearing CpG dinucleotides have...

  3. Clonal Selection Based Memetic Algorithm for Job Shop Scheduling Problems

    Institute of Scientific and Technical Information of China (English)

    Jin-hui Yang; Liang Sun; Heow Pueh Lee; Yun Qian; Yan-chun Liang


    A clonal selection based memetic algorithm is proposed for solving job shop scheduling problems in this paper. In the proposed algorithm, the clonal selection and the local search mechanism are designed to enhance exploration and exploitation. In the clonal selection mechanism, clonal selection, hypermutation and receptor edit theories are presented to construct an evolutionary searching mechanism which is used for exploration. In the local search mechanism, a simulated annealing local search algorithm based on Nowicki and Smutnicki's neighborhood is presented to exploit local optima. The proposed algorithm is examined using some well-known benchmark problems. Numerical results validate the effectiveness of the proposed algorithm.

  4. Clonality of HTLV-2 in natural infection.

    Directory of Open Access Journals (Sweden)

    Anat Melamed


    Full Text Available Human T-lymphotropic virus type 1 (HTLV-1 and type 2 (HTLV-2 both cause lifelong persistent infections, but differ in their clinical outcomes. HTLV-1 infection causes a chronic or acute T-lymphocytic malignancy in up to 5% of infected individuals whereas HTLV-2 has not been unequivocally linked to a T-cell malignancy. Virus-driven clonal proliferation of infected cells both in vitro and in vivo has been demonstrated in HTLV-1 infection. However, T-cell clonality in HTLV-2 infection has not been rigorously characterized. In this study we used a high-throughput approach in conjunction with flow cytometric sorting to identify and quantify HTLV-2-infected T-cell clones in 28 individuals with natural infection. We show that while genome-wide integration site preferences in vivo were similar to those found in HTLV-1 infection, expansion of HTLV-2-infected clones did not demonstrate the same significant association with the genomic environment of the integrated provirus. The proviral load in HTLV-2 is almost confined to CD8+ T-cells and is composed of a small number of often highly expanded clones. The HTLV-2 load correlated significantly with the degree of dispersion of the clone frequency distribution, which was highly stable over ∼8 years. These results suggest that there are significant differences in the selection forces that control the clonal expansion of virus-infected cells in HTLV-1 and HTLV-2 infection. In addition, our data demonstrate that strong virus-driven proliferation per se does not predispose to malignant transformation in oncoretroviral infections.

  5. TLR9 ligand (CpG oligodeoxynucleotide induces CLL B-cells to differentiate into CD20+ antibody-secreting cells

    Directory of Open Access Journals (Sweden)

    Hussein eGhamlouch


    Full Text Available B-cell chronic lymphocytic leukemia (CLL is the most frequent adult leukemia in the Western world. It is a heterogeneous disease characterized by clonal proliferation and the accumulation of CD5+ mature B lymphocytes. However, the normal counterpart from which the latter cells arise has not yet been identified. CD27 expression and gene expression profiling data suggest that CLL cells are related to memory B-cells. In vitro, memory B-cells differentiate into plasma cells when stimulated with CpG oligodeoxynucleotide (CpG. The objective of the present study was therefore to investigate the ability of CpG, in the context of CD40 ligation, to induce the differentiation of CLL B-cells into antibody-secreting cells (ASCs. CD20+CD38− CLL B-cells were stimulated with a combination of CpG, CD40 ligand and cytokines (CpG/CD40L/c in a two-step, seven-day culture system. We found that the CpG/CD40L/c culture system prompted CLL B-cells to differentiate into CD19+CD20+CD27+CD38- ASCs. These cells secreted large amounts of IgM and had the same shape as plasma cells. However, only IgMs secreted by ASCs that had differentiated from unmutated CLL B-cells were poly/autoreactive. Class-switch recombination to IgG and IgA was detected in cells expressing the activation-induced cytidine deaminase gene (AICDA. Although these ASCs expressed high levels of the transcription factors PRDM1 (BLIMP1, IRF4 and XBP1s, they did not downregulate expression of PAX5. Our results suggest that CLL B-cells can differentiate into ASCs, undergo class-switch recombination and produce poly/autoreactive antibodies. Furthermore, our findings may be relevant for (i identifying the normal counterpart of CLL B-cells and (ii developing novel treatment strategies in CLL.

  6. Differential Clonal Expansion in an Invading Cell Population: Clonal Advantage or Dumb Luck? (United States)

    Newgreen, Donald F; Zhang, Dongcheng; Cheeseman, Bevan L; Binder, Benjamin J; Landman, Kerry A


    In neoplastic cell growth, clones and subclones are variable both in size and mutational spectrum. The largest of these clones are believed to represent those cells with mutations that make them the most "fit," in a Darwinian sense, for expansion in their microenvironment. Thus, the degree of quantitative clonal expansion is regarded as being determined by innate qualitative differences between the cells that originate each clone. Here, using a combination of mathematical modelling and clonal labelling experiments applied to the developmental model system of the forming enteric nervous system, we describe how cells which are qualitatively identical may consistently produce clones of dramatically different sizes: most clones are very small while a few clones we term "superstars" contribute most of the cells to the final population. The basis of this is minor stochastic variations ("luck") in the timing and direction of movement and proliferation of individual cells, which builds a local advantage for daughter cells that is cumulative. This has potentially important consequences. In cancers, especially before strongly selective cytotoxic therapy, the assumption that the largest clones must be the cells with deterministic proliferative ability may not always hold true. In development, the gradual loss of clonal diversity as "superstars" take over the population may erode the resilience of the system to somatic mutations, which may have occurred early in clonal growth.

  7. The evidence for clonal spreading of quinolone resistance with a particular clonal complex of Campylobacter jejuni. (United States)

    Kovač, J; Cadež, N; Lušicky, M; Nielsen, E Møller; Ocepek, M; Raspor, P; Možina, S Smole


    Campylobacter is the most prevalent cause of bacterial gastroenteritis worldwide and it represents a significant public health risk of increasing severity due to its escalating resistance to clinically important quinolone and macrolide antibiotics. As a zoonotic pathogen Campylobacter is transmitted along the food chain and naturally cycles from environmental waters, feedstuff, animals and food to humans. We determined antibiotic resistance profiles, as well as multilocus sequence types and flaA-SVR types for 52 C. jejuni isolated in Slovenia from human, animal, raw and cured chicken meat and water samples. Twenty-eight different sequence types, arranged in ten clonal complexes, three new allele types and five new sequence types were identified, indicating the relatively high diversity in a small group of strains. The assignment of strains from different sources to the same clonal complexes indicates their transmission along the food supply chain. The most prevalent clonal complex was CC21, which was also the genetic group with 95% of quinolone-resistant strains. Based on the genetic relatedness of these quinolone-resistant strains identified by polymerase chain reaction with a mismatch amplification mutation assay and sequencing of the quinolone resistance-determining region of the gyrA gene, we conclude that the high resistance prevalence observed indicates the local clonal spread of quinolone resistance with CC21.

  8. Effects of patch contrast and arrangement on benefits of clonal integration in a rhizomatous clonal plant (United States)

    Wang, Yong-Jian; Shi, Xue-Ping; Wu, Xiao-Jing; Meng, Xue-Feng; Wang, Peng-Cheng; Zhou, Zhi-Xiang; Luo, Fang-Li; Yu, Fei-Hai


    The availabilities of light and soil water resources usually spatially co-vary in natural habitats, and the spatial pattern of such co-variation may affect the benefits of physiological integration between connected ramets of clonal plants. In a greenhouse experiment, we grew connected or disconnected ramet pairs [consisting of a proximal (relatively old) and a distal (relative young) ramet] of a rhizomatous herb Iris japonica in four heterogeneous environments differing in patch arrangement (reciprocal vs. parallel patchiness of light and soil water) and patch contrast (high vs. low contrast of light and water). Biomass of the proximal part, distal part and clonal fragment of I. japonica were all significantly greater in the intact than in the severed treatment, in the parallel than in the reciprocal patchiness treatment and in the high than in the low contrast treatment, but the effect of severing the connection between ramet pairs did not depend on patch arrangement or contrast. Severing the connection decreased number of ramets of the distal part and the clonal fragment in the parallel patchiness arrangement, but not in the reciprocal patchiness arrangement. Therefore, the spatial arrangement of resource patches can alter the effects of clonal integration on asexual reproduction in I. japonica. PMID:27759040

  9. Plate tectonics, damage and inheritance. (United States)

    Bercovici, David; Ricard, Yanick


    The initiation of plate tectonics on Earth is a critical event in our planet's history. The time lag between the first proto-subduction (about 4 billion years ago) and global tectonics (approximately 3 billion years ago) suggests that plates and plate boundaries became widespread over a period of 1 billion years. The reason for this time lag is unknown but fundamental to understanding the origin of plate tectonics. Here we suggest that when sufficient lithospheric damage (which promotes shear localization and long-lived weak zones) combines with transient mantle flow and migrating proto-subduction, it leads to the accumulation of weak plate boundaries and eventually to fully formed tectonic plates driven by subduction alone. We simulate this process using a grain evolution and damage mechanism with a composite rheology (which is compatible with field and laboratory observations of polycrystalline rocks), coupled to an idealized model of pressure-driven lithospheric flow in which a low-pressure zone is equivalent to the suction of convective downwellings. In the simplest case, for Earth-like conditions, a few successive rotations of the driving pressure field yield relic damaged weak zones that are inherited by the lithospheric flow to form a nearly perfect plate, with passive spreading and strike-slip margins that persist and localize further, even though flow is driven only by subduction. But for hotter surface conditions, such as those on Venus, accumulation and inheritance of damage is negligible; hence only subduction zones survive and plate tectonics does not spread, which corresponds to observations. After plates have developed, continued changes in driving forces, combined with inherited damage and weak zones, promote increased tectonic complexity, such as oblique subduction, strike-slip boundaries that are subparallel to plate motion, and spalling of minor plates.

  10. The role of Aire in clonal selection. (United States)

    Taniguchi, Ruth T; Anderson, Mark S


    In his clonal selection theory, Frank Macfarlane Burnet predicted that autoreactive lymphocytes are deleted to prevent autoimmunity. This and other principles of lymphocyte behavior outlined by Burnet guided many studies that lead to our current understanding of thymic selection. Thus, when the genetic mutation responsible for autoimmune polyglandular syndrome type 1 was mapped to the autoimmune regulator (AIRE) gene, and Aire was found to be highly expressed in thymic epithelium, studying the role of Aire in negative selection made sense in the context of modern models of thymic selection. We now know Aire is a transcription factor required for the expression of many tissue-specific antigens (TSAs) in the thymus. In the absence of functional Aire, human patients and mice develop multi-organ autoimmune disease because of a defect in thymic negative selection. In addition to its role in the thymus, recent work in our lab suggests that extrathymic Aire-expressing cells have an important role in the clonal deletion of autoreactive CD8+ T cells. In this review, we summarize the latest studies on thymic and peripheral Aire-expressing cells, as well as other TSA-expressing stromal cell populations in peripheral lymphoid organs. We also discuss theoretical differences in thymic and peripheral Aire function that warrant further studies.

  11. Immunodominance and clonal selection inspired multiobjective clustering

    Institute of Scientific and Technical Information of China (English)

    Wenping Ma; Licheng Jiao; Maoguo Gong


    The biological immune system is a highly parallel and distributed adaptive system. The information processing abilities of the immune system provide important insights into the field of computation. Based on immunodominance in the biological immune system and the clonal selection mechanism, a novel data mining method, Immune Dominance Clonal Multiobjective Clustering algorithm (IDCMC), is presented. The algorithm divides an individual population into three sub-populations according to three different measurements, and adopts different evolution and selection strategies for each sub-population. The update of each sub-population, however, is not carried out in isolation. The periodic combination operation of the analysis of the three sub-populations represents considerable advantages in its global search ability. The clustering task is a multiobjective optimization problem, which is more robust with respect to the variety of cluster structures of different datasets than a single-objective clustering algorithm. In addition, the new algorithm can determine the num-ber of clusters automatically, which should identify the most promising clustering solutions in the candidate set. The experimental results, using artificial datasets with different manifold structure and handwritten digit datasets, show that the IDCMC outperforms the PESA-ll-based clustering method, the genetic algorithm-based clustering technique and the original K-Means algorithm in solving most of the problems tested.

  12. Atypical mitochondrial inheritance patterns in eukaryotes. (United States)

    Breton, Sophie; Stewart, Donald T


    Mitochondrial DNA (mtDNA) is predominantly maternally inherited in eukaryotes. Diverse molecular mechanisms underlying the phenomenon of strict maternal inheritance (SMI) of mtDNA have been described, but the evolutionary forces responsible for its predominance in eukaryotes remain to be elucidated. Exceptions to SMI have been reported in diverse eukaryotic taxa, leading to the prediction that several distinct molecular mechanisms controlling mtDNA transmission are present among the eukaryotes. We propose that these mechanisms will be better understood by studying the deviations from the predominating pattern of SMI. This minireview summarizes studies on eukaryote species with unusual or rare mitochondrial inheritance patterns, i.e., other than the predominant SMI pattern, such as maternal inheritance of stable heteroplasmy, paternal leakage of mtDNA, biparental and strictly paternal inheritance, and doubly uniparental inheritance of mtDNA. The potential genes and mechanisms involved in controlling mitochondrial inheritance in these organisms are discussed. The linkage between mitochondrial inheritance and sex determination is also discussed, given that the atypical systems of mtDNA inheritance examined in this minireview are frequently found in organisms with uncommon sexual systems such as gynodioecy, monoecy, or andromonoecy. The potential of deviations from SMI for facilitating a better understanding of a number of fundamental questions in biology, such as the evolution of mtDNA inheritance, the coevolution of nuclear and mitochondrial genomes, and, perhaps, the role of mitochondria in sex determination, is considerable.

  13. Paternal inheritance of mitochondria in Chlamydomonas. (United States)

    Nakamura, Soichi


    To analyze mitochondrial DNA (mtDNA)inheritance, differences in mtDNA between Chlamydomonas reinhardtii and Chlamydomonas smithii, respiration deficiency and antibiotic resistance were used to distinguish mtDNA origins. The analyses indicated paternal inheritance. However, these experiments raised questions regarding whether paternal inheritance occurred normally.Mitochondrial nucleoids were observed in living zygotes from mating until 3 days after mating and then until progeny formation. However, selective disappearance of nucleoids was not observed. Subsequently, experimental serial backcrosses between the two strains demonstrated strict paternal inheritance. The fate of mt+ and mt- mtDNA was followed using the differences in mtDNA between the two strains. The slow elimination of mt+ mtDNA through zygote maturation in darkness was observed, and later the disappearance of mt+ mtDNA was observed at the beginning of meiosis. To explain the different fates of mtDNA, methylation status was investigated; however, no methylation was detected. Variously constructed diploid cells showed biparental inheritance. Thus, when the mating process occurs normally, paternal inheritance occurs. Mutations disrupting mtDNA inheritance have not yet been isolated. Mutations that disrupt maternal inheritance of chloroplast DNA (cpDNA) do not disrupt inheritance of mtDNA. The genes responsible for mtDNA inheritance are different from those of chloroplasts.

  14. CpG oligodeoxynucleotide nanomedicines for the prophylaxis or treatment of cancers, infectious diseases, and allergies (United States)

    Hanagata, Nobutaka


    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. PMID:28144136

  15. Epigenetic analysis of HIV-1 proviral genomes from infected individuals: predominance of unmethylated CpG's. (United States)

    Weber, Stefanie; Weiser, Barbara; Kemal, Kimdar S; Burger, Harold; Ramirez, Christina M; Korn, Klaus; Anastos, Kathryn; Kaul, Rupert; Kovacs, Colin; Doerfler, Walter


    Efforts to cure HIV-1 infections aim at eliminating proviral DNA. Integrated DNA from various viruses often becomes methylated de novo and transcriptionally inactivated. We therefore investigated CpG methylation profiles of 55 of 94 CpG's (58.5%) in HIV-1 proviral genomes including ten CpG's in each LTR and additional CpG's in portions of gag, env, nef, rev, and tat genes. We analyzed 33 DNA samples from PBMC's of 23 subjects representing a broad spectrum of HIV-1 disease. In 22 of 23 HIV-1-infected individuals, there were only unmethylated CpG's regardless of infection status. In one long term nonprogressor, however, methylation of proviral DNA varied between 0 and 75% over an 11-year period although the CD4+ counts remained stable. Hence levels of proviral DNA methylation can fluctuate. The preponderance of unmethylated CpG's suggests that proviral methylation is not a major factor in regulating HIV-1 proviral activity in PBMC's. Unmethylated CpG's may play a role in HIV-1 immunopathogenesis. © 2013 Elsevier Inc. All rights reserved.

  16. CpG islands undermethylation in human genomic regions under selective pressure.

    Directory of Open Access Journals (Sweden)

    Sergio Cocozza

    Full Text Available DNA methylation at CpG islands (CGIs is one of the most intensively studied epigenetic mechanisms. It is fundamental for cellular differentiation and control of transcriptional potential. DNA methylation is involved also in several processes that are central to evolutionary biology, including phenotypic plasticity and evolvability. In this study, we explored the relationship between CpG islands methylation and signatures of selective pressure in Homo Sapiens, using a computational biology approach. By analyzing methylation data of 25 cell lines from the Encyclopedia of DNA Elements (ENCODE Consortium, we compared the DNA methylation of CpG islands in genomic regions under selective pressure with the methylation of CpG islands in the remaining part of the genome. To define genomic regions under selective pressure, we used three different methods, each oriented to provide distinct information about selective events. Independently of the method and of the cell type used, we found evidences of undermethylation of CGIs in human genomic regions under selective pressure. Additionally, by analyzing SNP frequency in CpG islands, we demonstrated that CpG islands in regions under selective pressure show lower genetic variation. Our findings suggest that the CpG islands in regions under selective pressure seem to be somehow more "protected" from methylation when compared with other regions of the genome.

  17. Multi-layered multi-pattern CPG for adaptive locomotion of humanoid robots. (United States)

    Nassour, John; Hénaff, Patrick; Benouezdou, Fethi; Cheng, Gordon


    In this paper, we present an extended mathematical model of the central pattern generator (CPG) in the spinal cord. The proposed CPG model is used as the underlying low-level controller of a humanoid robot to generate various walking patterns. Such biological mechanisms have been demonstrated to be robust in locomotion of animal. Our model is supported by two neurophysiological studies. The first study identified a neural circuitry consisting of a two-layered CPG, in which pattern formation and rhythm generation are produced at different levels. The second study focused on a specific neural model that can generate different patterns, including oscillation. This neural model was employed in the pattern generation layer of our CPG, which enables it to produce different motion patterns-rhythmic as well as non-rhythmic motions. Due to the pattern-formation layer, the CPG is able to produce behaviors related to the dominating rhythm (extension/flexion) and rhythm deletion without rhythm resetting. The proposed multi-layered multi-pattern CPG model (MLMP-CPG) has been deployed in a 3D humanoid robot (NAO) while it performs locomotion tasks. The effectiveness of our model is demonstrated in simulations and through experimental results.

  18. All three classes of CpG ODNs up-regulate IP-10 gene in pigs. (United States)

    Dar, Arshud; Nichani, Anil; Lai, Ken; Potter, Andy; Gerdts, Volker; Babiuk, Lorne A; Mutwiri, George


    The analysis of CpG ODN induced innate immune responses in different animal species has shown substantial similarities and differences in levels and types of induced cytokines profile. The objectives of these studies were to identify innate immune biomarkers activated by three classes of CpG ODNs in pigs. For this purpose, we investigated the kinetics of innate immune responses in immune cells from pigs following in vitro and in vivo stimulation with CpG ODNs. The mRNA expression of cytokine and chemokine genes were assayed by SYBR green based quantitative real time PCR. A-class CpG ODN induced significant but transient levels of IFN-gamma, IL-12 (P40), IL-6, IL-4 and TNF-alpha mRNA, C-class CpG ODN induced significant level of IFN-gamma, IFN-alpha and IL-12 mRNA and the lowest level of IL-4 (Th-2 type) mRNA. A very low level of some cytokines stimulation was observed by GC ODNs. It is noteworthy, that IL-12 (P35) mRNA was significantly stimulated by B-class GpC ODN 7909. Interestingly, all classes of CpG ODNs induced significant level of IP-10 at 12h post stimulation. These in vitro and in vivo observations suggest that interferon-gamma inducible protein 10 (IP-10) may be a reliable biomarker for immune activity induced by CpG ODNs in pigs.

  19. Clonal architecture and patch formation of Potamogeton perfoliatus L. : in response to environmental conditions

    NARCIS (Netherlands)

    Wolfer, S.R.


    Keywords submersed macrophyte, P. perfoliatus, clonal architecture, spatial growth, shoot density, rhizome, biomass allocation, growth plasticity, foraging, allometry, sediment, porewater, nutrients, fertilization, clonal integration, individual-based model, Lake Constance Clonal growth governs t

  20. Mitochondrial DNA inheritance after SCNT. (United States)

    Hiendleder, Stefan


    Mitochondrial biogenesis and function is under dual genetic control and requires extensive interaction between biparentally inherited nuclear genes and maternally inherited mitochondrial genes. Standard SCNT procedures deprive an oocytes' mitochondrial DNA (mtDNA) of the corresponding maternal nuclear DNA and require it to interact with an entirely foreign nucleus that is again interacting with foreign somatic mitochondria. As a result, most SCNT embryos, -fetuses, and -offspring carry somatic cell mtDNA in addition to recipient oocyte mtDNA, a condition termed heteroplasmy. It is thus evident that somatic cell mtDNA can escape the selective mechanism that targets and eliminates intraspecific sperm mitochondria in the fertilized oocyte to maintain homoplasmy. However, the factors responsible for the large intra- and interindividual differences in heteroplasmy level remain elusive. Furthermore, heteroplasmy is probably confounded with mtDNA recombination. Considering the essential roles of mitochondria in cellular metabolism, cell signalling, and programmed cell death, future experiments will need to assess the true extent and impact of unorthodox mtDNA transmission on various aspects of SCNT success.

  1. Clonal distribution and virulence of Campylobacter jejuni isolates in blood. (United States)

    Feodoroff, Benjamin; de Haan, Caroline P A; Ellström, Patrik; Sarna, Seppo; Hänninen, Marja-Liisa; Rautelin, Hilpi


    Campylobacter jejuni bacteria are highly diverse enteropathogens. Seventy-three C. jejuni isolates from blood collected in Finland were analyzed by multilocus sequence typing and serum resistance. Approximately half of the isolates belonged to the otherwise uncommon sequence type 677 clonal complex. Isolates of this clonal complex were more resistant than other isolates to human serum.

  2. Cellular barcoding tool for clonal analysis in the hematopoietic system

    NARCIS (Netherlands)

    Gerrits, Alice; Dykstra, Brad; Kalmykowa, Olga J.; Klauke, Karin; Verovskaya, Evgenia; Broekhuis, Mathilde J. C.; de Haan, Gerald; Bystrykh, Leonid V.


    Clonal analysis is important for many areas of hematopoietic stem cell research, including in vitro cell expansion, gene therapy, and cancer progression and treatment. A common approach to measure clonality of retrovirally transduced cells is to perform integration site analysis using Southern blott

  3. Distribution of clonal growth traits among wetland habitats

    NARCIS (Netherlands)

    Sosnova, Monika; van Diggelen, Rudy; Macek, Petr; Klimesova, Jitka


    Clonality resulting from the growth of specialized organs is common among plants in wetland habitats. We hypothesize that different wetland habitats select for different attributes of clonal traits. This hypothesis is based on studies of individual species but has not been previously tested at the l

  4. Clonality Testing in Veterinary Medicine: A Review With Diagnostic Guidelines. (United States)

    Keller, S M; Vernau, W; Moore, P F


    The accurate distinction of reactive and neoplastic lymphoid proliferations can present challenges. Given the different prognoses and treatment strategies, a correct diagnosis is crucial. Molecular clonality assays assess rearranged lymphocyte antigen receptor gene diversity and can help differentiate reactive from neoplastic lymphoid proliferations. Molecular clonality assays are commonly used to assess atypical, mixed, or mature lymphoid proliferations; small tissue fragments that lack architecture; and fluid samples. In addition, clonality testing can be utilized to track neoplastic clones over time or across anatomic sites. Molecular clonality assays are not stand-alone tests but useful adjuncts that follow clinical, morphologic, and immunophenotypic assessment. Even though clonality testing provides valuable information in a variety of situations, the complexities and pitfalls of this method, as well as its dependency on the experience of the interpreter, are often understated. In addition, a lack of standardized terminology, laboratory practices, and interpretational guidelines hinders the reproducibility of clonality testing across laboratories in veterinary medicine. The objectives of this review are twofold. First, the review is intended to familiarize the diagnostic pathologist or interested clinician with the concepts, potential pitfalls, and limitations of clonality testing. Second, the review strives to provide a basis for future harmonization of clonality testing in veterinary medicine by providing diagnostic guidelines.

  5. Comprehensive analysis of CpG islands in human chromosomes 21 and 22 (United States)

    Takai, Daiya; Jones, Peter A.


    CpG islands are useful markers for genes in organisms containing 5-methylcytosine in their genomes. In addition, CpG islands located in the promoter regions of genes can play important roles in gene silencing during processes such as X-chromosome inactivation, imprinting, and silencing of intragenomic parasites. The generally accepted definition of what constitutes a CpG island was proposed in 1987 by Gardiner-Garden and Frommer [Gardiner-Garden, M. & Frommer, M. (1987) J. Mol. Biol. 196, 261-282] as being a 200-bp stretch of DNA with a C+G content of 50% and an observed CpG/expected CpG in excess of 0.6. Any definition of a CpG island is somewhat arbitrary, and this one, which was derived before the sequencing of mammalian genomes, will include many sequences that are not necessarily associated with controlling regions of genes but rather are associated with intragenomic parasites. We have therefore used the complete genomic sequences of human chromosomes 21 and 22 to examine the properties of CpG islands in different sequence classes by using a search algorithm that we have developed. Regions of DNA of greater than 500 bp with a G+C equal to or greater than 55% and observed CpG/expected CpG of 0.65 were more likely to be associated with the 5' regions of genes and this definition excluded most Alu-repetitive elements. We also used genome sequences to show strong CpG suppression in the human genome and slight suppression in Drosophila melanogaster and Saccharomyces cerevisiae. This finding is compatible with the recent detection of 5-methylcytosine in Drosophila, and might suggest that S. cerevisiae has, or once had, CpG methylation.

  6. Roles of Cell Division and Gene Transcription in the Methylation of CpG Islands (United States)

    Bender, Christina M.; Gonzalgo, Mark L.; Gonzales, Felicidad A.; Nguyen, Carvell T.; Robertson, Keith D.; Jones, Peter A.


    De novo methylation of CpG islands within the promoters of eukaryotic genes is often associated with their transcriptional repression, yet the methylation of CpG islands located downstream of promoters does not block transcription. We investigated the kinetics of mRNA induction, demethylation, and remethylation of the p16 promoter and second-exon CpG islands in T24 cells after 5-aza-2′-deoxycytidine (5-Aza-CdR) treatment to explore the relationship between CpG island methylation and gene transcription. The rates of remethylation of both CpG islands were associated with time but not with the rate of cell division, and remethylation of the p16 exon 2 CpG island occurred at a higher rate than that of the p16 promoter. We also examined the relationship between the remethylation of coding sequence CpG islands and gene transcription. The kinetics of remethylation of the p16 exon 2, PAX-6 exon 5, c-ABL exon 11, and MYF-3 exon 3 loci were examined following 5-Aza-CdR treatment because these genes contain exonic CpG islands which are hypermethylated in T24 cells. Remethylation occurred most rapidly in the p16, PAX-6, and c-ABL genes, shown to be transcribed prior to drug treatment. These regions also exhibited higher levels of remethylation in single-cell clones and subclones derived from 5-Aza-CdR-treated T24 cells. Our data suggest that de novo methylation is not restricted to the S phase of the cell cycle and that transcription through CpG islands does not inhibit their remethylation. PMID:10490608

  7. Kin Recognition in a Clonal Fish, Poecilia formosa (United States)

    Makowicz, Amber M.; Tiedemann, Ralph; Schlupp, Ingo


    Relatedness strongly influences social behaviors in a wide variety of species. For most species, the highest typical degree of relatedness is between full siblings with 50% shared genes. However, this is poorly understood in species with unusually high relatedness between individuals: clonal organisms. Although there has been some investigation into clonal invertebrates and yeast, nothing is known about kin selection in clonal vertebrates. We show that a clonal fish, the Amazon molly (Poecilia formosa), can distinguish between different clonal lineages, associating with genetically identical, sister clones, and use multiple sensory modalities. Also, they scale their aggressive behaviors according to the relatedness to other females: they are more aggressive to non-related clones. Our results demonstrate that even in species with very small genetic differences between individuals, kin recognition can be adaptive. Their discriminatory abilities and regulation of costly behaviors provides a powerful example of natural selection in species with limited genetic diversity. PMID:27483372




    Inherited neuropathy is a group of common neurologic disorders with heterogeneous clinical presentations and genetic causes. Detailed neuromuscular evaluations, including nerve conduction studies, laboratory testing, and histopathologic examination, can assist in identification of the inherited component beyond family history. Genetic testing increasingly enables definitive diagnosis of specific inherited neuropathies. Diagnosis, however, is often complex, and neurologic disability may have both genetic and acquired components in individual patients. The decision of which genetic test to order or whether to order genetic tests is often complicated, and the strategies to maximize the value of testing are evolving. Apart from rare inherited metabolic neuropathies, treatment approaches remain largely supportive. We provide a clinical update of the various types of inherited neuropathies, their differential diagnoses, and distinguishing clinical features (where available). A framework is provided for clinical evaluations, including the inheritance assessment, electrophysiologic examinations, and specific genetic tests. PMID:23801417

  9. Immunogenicity and safety of liposome-vaccine encapsulating hepatitis B surface antigen and phosphodiester CpG oligodeoxynucleotides

    Institute of Scientific and Technical Information of China (English)



    CpG oligodeoxynucleotides (CpG ODN) as adjuvant have been extensively studied in recent years. Phosphodiester CpG ODN (PO CpG ODN) can perfectly mimic bacterial DNA in enhancing immune response but are vulnerable to nucleases in vivo. This study aimed to evaluate the immunostimu latory potential and safety of phosphodiester CpG ODN encapsulated in nonphospholipid liposomes.BALB/c mice were immunized intramuscularly with different formulations of liposomes, CpG ODN and hepatitis B surface antigen (HBsAg). The results demonstrated that the encapsulated PO CpG ODN were protected against rapid degradation in vivo and retained their adjuvant activity. PO CpG ODN encapsulated with HBsAg in liposomes induced strong Th1-biased or Th1/Th2 mixed humoral immune response in mice with the magnitude similar to their phosphothioate equivalent in the same formulation.High IFN-gamma production induced by this formulation confirmed the generation of strong cellular immune response. Additionally, co-delivery of HBsAg and PO CpG ODN improved the immune response over that obtained with separate delivery. Safety experiment showed that liposome-encapsulaed PO CpG ODN and HBsAg caused mild systemic and moderate local adverse reaction. In conclusion, our data shows that PO CpG ODN encapsulated in liposomes fully exhibit their Th1-type adjuvant activity and act as a potential adjuvant for vaccines.

  10. Inheritance of goat coat colors. (United States)

    Adalsteinsson, S; Sponenberg, D P; Alexieva, S; Russel, A J


    Goat color inheritance was evaluated based on color description of 218 kids and their parents (10 sires, 178 dams) from mixed crosses between several goat populations in an experiment on cashmere fiber production. Altogether 10 color patterns were observed. They were postulated to be caused by 10 alleles at the Agouti locus, with the allele for white or tan color being the top dominant allele, and the nine others codominant. The bottom recessive allele, for nonagouti color, was the 11th allele at this locus. The postulated alleles are white or tan (A(wt)), black mask (A(blm)), bezoar (A(bz)), badgerface (A(b)), grey (A(g)), lightbelly (A(lb)), swiss markings (A(sm)), lateral stripes (A(ls)), mahogany (A(mh)), red cheek (A(rc)), and nonagouti (Aa). Two types of eumelanin pigment were observed, black and light brown, the latter being dominant. Recessive brown was not observed.

  11. Regulation of DNA transposition by CpG methylation and chromatin structure in human cells. (United States)

    Jursch, Tobias; Miskey, Csaba; Izsvák, Zsuzsanna; Ivics, Zoltán


    The activity of transposable elements can be regulated by different means. DNA CpG methylation is known to decrease or inhibit transpositional activity of diverse transposons. However, very surprisingly, it was previously shown that CpG methylation of the Sleeping Beauty (SB) transposon significantly enhanced transposition in mouse embryonic stem cells. In order to investigate the unexpected response of SB transposition to CpG methylation, related transposons from the Tc1/mariner superfamily, that is, Tc1, Himar1, Hsmar1, Frog Prince (FP) and Minos were tested to see how transposition was affected by CpG methylation. A significant increase of >20-fold in transposition of SB, FP and Minos was seen, whereas Tc1, Himar1 and Hsmar1 showed no difference in transposition upon CpG-methylation. The terminal inverted repeats (TIRs) of the SB, FP and Minos elements share a common structure, in which each TIR contains two functionally important binding sites for the transposase (termed the IR/DR structure). The group of IR/DR elements showed increased excision after CpG methylation compared to untreated transposon donor plasmids. We found that de novo CpG methylation is not required for transposition. A mutated FP donor plasmid with depleted CpG sites in both TIRs was as efficient in transposition as the wild-type transposon, indicating that CpG sites inside the TIRs are not responsible for altered binding of factors potentially modulating transposition. By using an in vivo one-hybrid DNA-binding assay in cultured human cells we found that CpG methylation had no appreciable effect on the affinity of SB transposase to its binding sites. However, chromatin immunoprecipitation indicated that CpG-methylated transposon donor plasmids are associated with a condensed chromatin structure characterized by trimethylated histone H3K9. Finally, DNA compaction by protamine was found to enhance SB transposition. We have shown that DNA CpG methylation upregulates transposition of IR

  12. Analysis of CpG methylation sites and CGI among human papillomavirus DNA genomes

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    Galván Silvia C


    Full Text Available Abstract Background The Human Papillomavirus (HPV genome is divided into early and late coding sequences, including 8 open reading frames (ORFs and a regulatory region (LCR. Viral gene expression may be regulated through epigenetic mechanisms, including cytosine methylation at CpG dinucleotides. We have analyzed the distribution of CpG sites and CpG islands/clusters (CGI among 92 different HPV genomes grouped in function of their preferential tropism: cutaneous or mucosal. We calculated the proportion of CpG sites (PCS for each ORF and calculated the expected CpG values for each viral type. Results CpGs are underrepresented in viral genomes. We found a positive correlation between CpG observed and expected values, with mucosal high-risk (HR virus types showing the smallest O/E ratios. The ranges of the PCS were similar for most genomic regions except E4, where the majority of CpGs are found within islands/clusters. At least one CGI belongs to each E2/E4 region. We found positive correlations between PCS for each viral ORF when compared with the others, except for the LCR against four ORFs and E6 against three other ORFs. The distribution of CpG islands/clusters among HPV groups is heterogeneous and mucosal HR-HPV types exhibit both lower number and shorter island sizes compared to cutaneous and mucosal Low-risk (LR HPVs (all of them significantly different. Conclusions There is a difference between viral and cellular CpG underrepresentation. There are significant correlations between complete genome PCS and a lack of correlations between several genomic region pairs, especially those involving LCR and E6. L2 and L1 ORF behavior is opposite to that of oncogenes E6 and E7. The first pair possesses relatively low numbers of CpG sites clustered in CGIs while the oncogenes possess a relatively high number of CpG sites not associated to CGIs. In all HPVs, E2/E4 is the only region with at least one CGI and shows a higher content of CpG sites in every

  13. CpG ODN 免疫佐剂效应研究进展%Progress on Immunoadjuvant Effect of CpG ODN

    Institute of Scientific and Technical Information of China (English)

    董鹏; 程世鹏; 李真光; 杨洺扬; 胡桂学; 冷雪


    Synthetic oligodeoxynucleotides containing CpG motifs (CpG ODN)could combine with Toll-like receptor 9 (TLR-9)on endoplasmic reticulum from dendritic cells,B cells,monocytes and macrophages to mount an immune response characterized by the production of Th1 and proinflammatory cytokines,as an immune enhancer to resistance to pathogen invasion and antitumor in the hosts.In recent years,CpG ODN as a new immune adjuvant has received more attention.This article mainly introduced the research progress on the kinds of CpG ODN and its structure and function characteristics,mechanisms of action,immune en-hancement livestock and poultry in to strengthen and safety for CpG ODN as vaccine adjuvants to offer ref-erence to further research and its veterinary usage in clinic.%人工合成的含非甲基化 CpG 基序的寡聚脱氧核苷酸(CpG ODN)能够与树突状细胞、B 细胞、单核细胞及巨噬细胞等免疫细胞内质网膜上的 Toll 样受体9(TLR-9)结合,通过产生 Th1型免疫反应和分泌促炎因子来增强免疫应答的强度,在机体抵抗病原入侵和抗肿瘤等方面起到免疫增强剂的作用。近年来, CpG ODN 作为一种新型免疫佐剂受到了人们越来越多的关注。论文主要介绍了 CpG ODN 的种类及其结构和功能特征、作用机制、对畜禽的免疫增强作用、安全性等方面的研究进展,为 CpG ODN 作为疫苗佐剂的进一步研究和在兽医临床上的应用提供参考。

  14. Real-time Walking Pattern Generation for a Biped Robot with Hybrid CPG-ZMP Algorithm

    Directory of Open Access Journals (Sweden)

    Bin He


    Full Text Available Biped robots have better mobility than conventional wheeled robots. The bio-inspired method based on a central pattern generator (CPG can be used to control biped robot walking in a manner like human beings. However, to achieve stable locomotion, it is difficult to modulate the parameters for the neural networks to coordinate every degree of freedom of the walking robot. The zero moment point (ZMP method is very popular for the stability control of biped robot walking. However, the reference trajectories have low energy efficiency, lack naturalness and need significant offline calculation. This paper presents a new method for biped real-time walking generation using a hybrid CPG-ZMP control algorithm. The method can realize a stable walking pattern by combining the ZMP criterion with rhythmic motion control. The CPG component is designed to generate the desired motion for each robot joint, which is modulated by phase resetting according to foot contact information. By introducing the ZMP location, the activity of the CPG output signal is adjusted to coordinate the limbs’ motion and allow the robot to maintain balance during the process of locomotion. The numerical simulation results show that, compared with the CPG method, the new hybrid CPG-ZMP algorithm can enhance the robustness of the CPG parameters and improve the stability of the robot. In addition, the proposed algorithm is more energy efficient than the ZMP method. The results also demonstrate that the control system can generate an adaptive walking pattern through interactions between the robot, the CPG and the environment.

  15. Cellular barcoding tool for clonal analysis in the hematopoietic system. (United States)

    Gerrits, Alice; Dykstra, Brad; Kalmykowa, Olga J; Klauke, Karin; Verovskaya, Evgenia; Broekhuis, Mathilde J C; de Haan, Gerald; Bystrykh, Leonid V


    Clonal analysis is important for many areas of hematopoietic stem cell research, including in vitro cell expansion, gene therapy, and cancer progression and treatment. A common approach to measure clonality of retrovirally transduced cells is to perform integration site analysis using Southern blotting or polymerase chain reaction-based methods. Although these methods are useful in principle, they generally provide a low-resolution, biased, and incomplete assessment of clonality. To overcome those limitations, we labeled retroviral vectors with random sequence tags or "barcodes." On integration, each vector introduces a unique, identifiable, and heritable mark into the host cell genome, allowing the clonal progeny of each cell to be tracked over time. By coupling the barcoding method to a sequencing-based detection system, we could identify major and minor clones in 2 distinct cell culture systems in vitro and in a long-term transplantation setting. In addition, we demonstrate how clonal analysis can be complemented with transgene expression and integration site analysis. This cellular barcoding tool permits a simple, sensitive assessment of clonality and holds great promise for future gene therapy protocols in humans, and any other applications when clonal tracking is important.

  16. IGF2/H19 hypomethylation is tissue, cell, and CpG site dependent and not correlated with body asymmetry in adolescents with Silver-Russell syndrome

    Directory of Open Access Journals (Sweden)

    Kannenberg Kai


    Full Text Available Abstract Background Silver-Russell syndrome (SRS is characterized by severe intrauterine and postnatal growth failure and frequent body asymmetry. Half of the patients with SRS carry a DNA hypomethylation of the imprinting center region 1 (ICR1 of the insulin-like growth factor 2 (IGF2/H19 locus, and the clinical phenotype is most severe in these patients. We aimed to elucidate the epigenetic basis of asymmetry in SRS and the cellular consequences of the ICR1 hypomethylation. Results The ICR1 methylation status was analyzed in blood and in addition in buccal smear probes and cultured fibroblasts obtained from punch biopsies taken from the two body halves of 5 SRS patients and 3 controls. We found that the ICR1 hypomethylation in SRS patients was stronger in blood leukocytes and oral mucosa cells than in fibroblasts. ICR1 CpG sites were affected differently. The severity of hypomethylation was not correlated to body asymmetry. IGF2 expression and IGF-II secretion of fibroblasts were not correlated to the degree of ICR1 hypomethylation. SRS fibroblasts responded well to stimulation by recombinant human IGF-I or IGF-II, with proliferation rates comparable with controls. Clonal expansion of primary fibroblasts confirmed the complexity of the cellular mosaicism. Conclusions We conclude that the ICR1 hypomethylation SRS is tissue, cell, and CpG site specific. The correlation of the ICR1 hypomethylation to IGF2 and H19 expression is not strict, may depend on the investigated tissue, and may become evident only in case of more severe methylation defects. The body asymmetry in juvenile SRS patients is not related to a corresponding ICR1 hypomethylation gradient, rendering more likely an intrauterine origin of asymmetry. Overall, it may be instrumental to consider not only the ICR1 methylation status as decisive for IGF2/H19 expression regulation.

  17. Design of a cyclic inhibitory CPG controller for the locomotion of a snakelike robot

    Institute of Scientific and Technical Information of China (English)

    LU Zhen-li; MA Shu-gen; LI Bin; WANG Yue-chao


    The rhythmic locomotion of a creature is a serf-excitation behavior of the CPG (central pattern generator),which makes it supremely adapted for environment.Based on this fact,firstly,a snake-like robot controller with cyclic inhibitory CPG model was designed,and then the stability of a single neuron,CPG model and the NON(neuron oscillator network) was analyzed.By implementing this control architecture to a simulator based on the mechanical dynamics of a real snake-like robot named Perambulator-I,we presented preliminary rules for parameter setting of the CPG controller to modulate the number of S shapes,the curve of the body shape,locomotion velocity,and the curve of the locomotion trajectory for serpentine locomotion.Moreover,we demonstrated that Perambulator-I can successfully exhibit serpentine locomotion by using the output of the proposed CPG controller.The results of this paper provide a realistic approach for designing an artificial CPG controller.

  18. CpG oligodeoxynucleotides with crude parasite antigens reduce worm recovery in Opisthorchis viverrini infected hamsters. (United States)

    Kaewraemruaen, Chamraj; Sermswan, Rasana W; Wongratanacheewin, Surasakdi


    Opisthorchis viverrini, a human liver fluke, is still an endemic parasitic infection in Thailand and nearly all countries in Southeast Asia. O. viverrini induces a chronic stage of infection in hamsters. During the first 2 weeks of infection, Th1 inducing cytokine, IL-12, increased but was down regulated in chronic infection. In this study it was found that unmethylated-CpG ODN (oligodeoxynucleotides) 1826 increased hamster mononuclear cell proliferation and stimulated IFN-γ production in vitro. The IFN-γ levels in hamster sera were significantly increased in hamsters injected with CpG ODN 1826 alone or plus crude somatic antigens (CSAg). Further investigation using the flow cytometer found that CD4(+)T cells and IFN-γ(+) CD4(+)T cells (Th1-like cells) in the hamster blood were significantly increased. The role of these cells in the protective responses in hamsters was evaluated by challenging with 25 metacercaria and observation for 3 months. The number of worms recovered was significantly reduced in the hamsters injected with CpG ODN 1826 with CSAg, but not in CpG ODN 1826 alone groups when compared to PBS control. The percent of reduction in hamsters against this parasite were 32.95% and 21.49% in the CpG ODN 1826 with CSAg and CpG ODN 1826 alone. This study indicates that CpG ODN 1826 plus parasite antigens elicit a Th1-like response that leads to the enhancement of worm reduction.

  19. CpG ODN Enhances Immunization Effects of Hepatitis B Vaccine in Aged Mice

    Institute of Scientific and Technical Information of China (English)

    Weibing Qin; Jianwei Jiang; Qiaoer Chen; Ning Yang; Yifeng Wang; Xiangcai Wei; Ruqiang Ou


    Oligodeoxynucleotides (ODN) containing unmethylated CpG dinucleotides in contexts of unique sequence (CpG motifs) is active as adjuvant in induction of cellular and humoral immune responses in young mice. To date, there are only limited reports about effect of CpG ODN on immune responses against hepatitis B (HB) infection in aged mice. Our studies demonstrated there were significant increases in secreting of total anti-HB IgG, IgG1 and IgG2a, as well as of IL-12 and IFN-γ, when CpG ODNs were injected together with hepatitis B antigen in aged mice. Moreover, CpG ODN could stimulate proliferation of spleen lymphocytes in a dose-dependent manner. Taken together, the results we obtained indicate that the adding of CpG ODN into the vaccine antigen might be useful in development of more effective vaccination for inducing anti-HB virus responses in the elderly.

  20. Nucleosome dynamics and maintenance of epigenetic states of CpG islands (United States)

    Sneppen, Kim; Dodd, Ian B.


    Methylation of mammalian DNA occurs primarily at CG dinucleotides. These CpG sites are located nonrandomly in the genome, tending to occur within high density clusters of CpGs (islands) or within large regions of low CpG density. Cluster methylation tends to be bimodal, being dominantly unmethylated or mostly methylated. For CpG clusters near promoters, low methylation is associated with transcriptional activity, while high methylation is associated with gene silencing. Alternative CpG methylation states are thought to be stable and heritable, conferring localized epigenetic memory that allows transient signals to create long-lived gene expression states. Positive feedback where methylated CpG sites recruit enzymes that methylate nearby CpGs, can produce heritable bistability but does not easily explain that as clusters increase in size or density they change from being primarily methylated to primarily unmethylated. Here, we show that an interaction between the methylation state of a cluster and its occupancy by nucleosomes provides a mechanism to generate these features and explain genome wide systematics of CpG islands.

  1. CpG ODN Enhances Immunization Effects of Hepatitis B Vaccine in Aged Mice

    Institute of Scientific and Technical Information of China (English)

    WeibingQin; JianweiJiang; QiaoerChen; NingYang; YifengWang; XiangcaiWei; RuqiangOu


    Oligodeoxynucleotides (ODN) containing unmethylated CpG dinucleotides in contexts of unique sequence (CpG motifs) is active as adjuvant in induction of cellular and humoral immune responses in young mice. To date, there are only limited reports about effect of CpG ODN on immune responses against hepatitis B (HB) infection in aged mice. Our studies demonstrated there were significant increases in secreting of total anti-HB IgG, IgG1 and IgG2a, as well as of IL-12 and IFN-γ, when CpG ODNs were injected together with hepatitis B antigen in aged mice. Moreover, CpG ODN could stimulate proliferation of spleen lymphocytes in a dose-dependent manner. Taken together, the results we obtained indicate that the adding of CpG ODN into the vaccine antigen might be useful in development of more effective vaccination for inducing anti-HB virus responses in the elderly. Cellular & Molecular Immunology. 2004;1(2):148-152.

  2. Least Privileges and Role's Inheritance of RBAC

    Institute of Scientific and Technical Information of China (English)


    The main advantages of role-based access control (RBAC) are able to support the well-known security principles and roles' inheritance. But for there remains a lack of specific definition and the necessary formalization for RBAC, it is hard to realize RBAC in practical work. Our contribution here is to formalize the main relations of RBAC and take first step to propose concepts of action closure and data closure of a role, based on which we got the specification and algorithm for the least privileges of a role. We propose that roles' inheritance should consist of inheritance of actions and inheritance of data, and then we got the inheritance of privileges among roles, which can also be supported by existing exploit tools.

  3. Transgenerational epigenetic inheritance in health and disease. (United States)

    Whitelaw, Nadia C; Whitelaw, Emma


    Over the past century, patterns of phenotypic inheritance have been observed that are not easily rationalised by Mendel's rules of inheritance. Now that we have begun to understand more about non-DNA based, or 'epigenetic', control of phenotype at the molecular level, the idea that the transgenerational inheritance of these epigenetic states could explain non-Mendelian patterns of inheritance has become attractive. There is a growing body of evidence that abnormal epigenetic states, termed epimutations, are associated with disease in humans. For example, in several cases of colorectal cancer, epimutations have been identified that silence the human mismatch repair genes, MLH1 and MSH2. But strong evidence that the abnormal epigenetic states are primary events that occur in the absence of genetic change and are inherited across generations is still absent.

  4. Identification of a boron nitride nanosphere-binding peptide for the intracellular delivery of CpG oligodeoxynucleotides (United States)

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


    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

  5. Coalgebraic structure of genetic inheritance. (United States)

    Tian, Jianjun; Li, Bai-Lian


    Although in the broadly defined genetic algebra, multiplication suggests a forward direction of from parents to progeny, when looking from the reverse direction, it also suggests to us a new algebraic structure-coalge- braic structure, which we call genetic coalgebras. It is not the dual coalgebraic structure and can be used in the construction of phylogenetic trees. Math- ematically, to construct phylogenetic trees means we need to solve equations x([n]) = a, or x([n]) = b. It is generally impossible to solve these equations inalgebras. However, we can solve them in coalgebras in the sense of tracing back for their ancestors. A thorough exploration of coalgebraic structure in genetics is apparently necessary. Here, we develop a theoretical framework of the coalgebraic structure of genetics. From biological viewpoint, we defined various fundamental concepts and examined their elementary properties that contain genetic significance. Mathematically, by genetic coalgebra, we mean any coalgebra that occurs in genetics. They are generally noncoassociative and without counit; and in the case of non-sex-linked inheritance, they are cocommutative. Each coalgebra with genetic realization has a baric property. We have also discussed the methods to construct new genetic coalgebras, including cocommutative duplication, the tensor product, linear combinations and the skew linear map, which allow us to describe complex genetic traits. We also put forward certain theorems that state the relationship between gametic coalgebra and gametic algebra. By Brower's theorem in topology, we prove the existence of equilibrium state for the in-evolution operator.

  6. Leading the Team You Inherit. (United States)

    Watkins, Michael D


    Most leaders don't have the luxury of building their teams from scratch. Instead they're put in charge of an existing group, and they need guidance on the best way to take over and improve performance. Watkins, an expert on transitions, suggests a three-step approach: Assess. Act quickly to size up the personnel you've inherited, systematically gathering data from one-on-one chats, team meetings, and other sources. Reflect, too, on the business challenges you face, the kinds of people you want in various roles, and the degree to which they need to collaborate. Reshape. Adjust the makeup of the team by moving people to new positions, shifting their responsibilities, or replacing them. Make sure that everyone is aligned on goals and how to achieve them--you may need to change the team's stated direction. Consider also making changes in the way the team operates (reducing the frequency of meetings, for example, or creating new subteams). Then establish ground rules and processes to sustain desired behaviors, and revisit those periodically. Accelerate team development. Set your people up for some early wins. Initial successes will boost everyone's confidence and reinforce the value of your new operating model, thus paving the way for ongoing growth.

  7. Safety and immunogenicity of CPG 7909 injection as an adjuvant to Fluarix influenza vaccine. (United States)

    Cooper, C L; Davis, H L; Morris, M L; Efler, S M; Krieg, A M; Li, Y; Laframboise, C; Al Adhami, M J; Khaliq, Y; Seguin, I; Cameron, D W


    CPG 7909, a 24-mer B-Class CpG oligodeoxynucleotide (ODN), was tested for safety, tolerability and its ability to augment the immunogenicity of a commercial trivalent killed split influenza vaccine (Fluarix containing A/Beijing/262/95, A/Sydney/5/97 and B/Harbin/7/94; SmithKline Beecham) in a phase Ib blinded, randomized, controlled clinical trial. Sixty healthy volunteers were recruited in two consecutive cohorts of 30 subjects, who were randomly assigned to receive Fluarix plus 1mg CPG 7909 or Fluarix plus saline control (15 subjects each). Vaccines were administered by intramuscular injection on a single occasion with subjects in the first cohort receiving a 1/10th dose of Fluarix and those in the second cohort receiving the full-dose. All safety measures including physical evaluation, laboratory blood assays, and assays for DNA autoimmunity were within normal values except for transient and clinically inconsequential decreases in total white blood cell counts in groups receiving CPG 7909. All vaccines were found to be generally well tolerated with similar frequency and intensity for most adverse reactions for groups receiving CPG 7909 as controls. Exceptions were injection site pain and headache, which were reduced in frequency in subjects receiving the 1/10th Fluarix dose without CpG, compared to the frequency in all other groups. There was a lack of pre-existing immunity, defined as hemagglutinin inhibition (HI) activity CPG 7909, except in individuals with pre-existing immunity to A/Sydney/5/97 strain (baseline HI activity titre >20), where there was a trend to higher HI activity with CPG 7909 (P = 0.06). The addition of CPG 7909 to the 1/10th dose of Fluarix did however result in significantly higher levels of IFN-gamma secretion from peripheral blood mononuclear cells recovered at 4 weeks and restimulated ex vivo with A/Beijing/262/95 (P = 0.048) and B/Harbin/7/94 (P = 0.0057), restoring these to the level seen with full-dose vaccine. These results suggest

  8. Clonal Expansion (CE) Models in Cancer Risk Assessment (United States)

    Cancer arises when cells accumulate sufficient critical mutations. Carcinogens increase the probability of mutation during cell division or promote clonal expansion within stages. Multistage CE models recapitulate this process and provide a framework for incorporating relevant da...

  9. Adjusting to global change through clonal growth and epigenetic variation

    Directory of Open Access Journals (Sweden)

    Richard S Dodd


    Full Text Available The earth is experiencing major changes in global and regional climates and changes are predicted to accelerate in the future. Many species will be under considerable pressure to evolve, to migrate, or be faced with extinction. Clonal plants would appear to be at a particular disadvantage due to their limited mobility and limited capacity for adaptation. However, they have outlived previous environmental shifts and clonal species have persisted for millenia. Clonal spread offers unique ecological advantages, such as resource sharing, risk sharing, and economies of scale among ramets within genotypes. We suggest that ecological attributes of clonal plants, in tandem with variation in gene regulation through epigenetic mechanisms that facilitate and optimize phenotype variation in response to environmental change may permit them to be well suited to projected conditions.

  10. Texture Pattern Generation Using Clonal Mosaic

    Institute of Scientific and Technical Information of China (English)

    How Jiann Teo; Kok Cheong Wong


    In this paper, an effective system for synthesizing animal skin patterns on arbitrary polygonal surfaces is developed. To accomplish the task, a system inspired by the Clonal Mosaic (CM) model is proposed. The CM model simulates cells' reactions on arbitrary surface. By controlling the division, mutation and repulsion of cells, a regulated spatial arrangement of cells is formed. This arrangement of cells shows appealing result, which is comparable with those natural patterns observed from animal skin. However, a typical CM simulation process incurs high computational cost, where the distances among cells across a polygonal surface are measured and the movements of cells are constrained on the surface. In this framework, an approach is proposed to transform each of the original 3D geometrical planes of the surface into its Canonical Reference Plane Structure. This structure helps to simplify a 3D computational problem into a more manageable 2D problem. Furthermore, the concept of Local Relaxation is developed to optimally enhance the relaxation process for a typical CM simulation. The performances of the proposed solution methods have been verified with extensive experimental results.

  11. Divergent clonal selection dominates medulloblastoma at recurrence (United States)

    Morrissy, A. Sorana; Garzia, Livia; Shih, David J. H.; Zuyderduyn, Scott; Huang, Xi; Skowron, Patryk; Remke, Marc; Cavalli, Florence M. G.; Ramaswamy, Vijay; Lindsay, Patricia E.; Jelveh, Salomeh; Donovan, Laura K.; Wang, Xin; Luu, Betty; Zayne, Kory; Li, Yisu; Mayoh, Chelsea; Thiessen, Nina; Mercier, Eloi; Mungall, Karen L.; Ma, Yusanne; Tse, Kane; Zeng, Thomas; Shumansky, Karey; Roth, Andrew J. L.; Shah, Sohrab; Farooq, Hamza; Kijima, Noriyuki; Holgado, Borja L.; Lee, John J. Y.; Matan-Lithwick, Stuart; Liu, Jessica; Mack, Stephen C.; Manno, Alex; Michealraj, K. A.; Nor, Carolina; Peacock, John; Qin, Lei; Reimand, Juri; Rolider, Adi; Thompson, Yuan Y.; Wu, Xiaochong; Pugh, Trevor; Ally, Adrian; Bilenky, Mikhail; Butterfield, Yaron S. N.; Carlsen, Rebecca; Cheng, Young; Chuah, Eric; Corbett, Richard D.; Dhalla, Noreen; He, An; Lee, Darlene; Li, Haiyan I.; Long, William; Mayo, Michael; Plettner, Patrick; Qian, Jenny Q.; Schein, Jacqueline E.; Tam, Angela; Wong, Tina; Birol, Inanc; Zhao, Yongjun; Faria, Claudia C.; Pimentel, José; Nunes, Sofia; Shalaby, Tarek; Grotzer, Michael; Pollack, Ian F.; Hamilton, Ronald L.; Li, Xiao-Nan; Bendel, Anne E.; Fults, Daniel W.; Walter, Andrew W.; Kumabe, Toshihiro; Tominaga, Teiji; Collins, V. Peter; Cho, Yoon-Jae; Hoffman, Caitlin; Lyden, David; Wisoff, Jeffrey H.; Garvin, James H.; Stearns, Duncan S.; Massimi, Luca; Schüller, Ulrich; Sterba, Jaroslav; Zitterbart, Karel; Puget, Stephanie; Ayrault, Olivier; Dunn, Sandra E.; Tirapelli, Daniela P. C.; Carlotti, Carlos G.; Wheeler, Helen; Hallahan, Andrew R.; Ingram, Wendy; MacDonald, Tobey J.; Olson, Jeffrey J.; Van Meir, Erwin G.; Lee, Ji-Yeoun; Wang, Kyu-Chang; Kim, Seung-Ki; Cho, Byung-Kyu; Pietsch, Torsten; Fleischhack, Gudrun; Tippelt, Stephan; Ra, Young Shin; Bailey, Simon; Lindsey, Janet C.; Clifford, Steven C.; Eberhart, Charles G.; Cooper, Michael K.; Packer, Roger J.; Massimino, Maura; Garre, Maria Luisa; Bartels, Ute; Tabori, Uri; Hawkins, Cynthia E.; Dirks, Peter; Bouffet, Eric; Rutka, James T.; Wechsler-Reya, Robert J.; Weiss, William A.; Collier, Lara S.; Dupuy, Adam J.; Korshunov, Andrey; Jones, David T. W.; Kool, Marcel; Northcott, Paul A.; Pfister, Stefan M.; Largaespada, David A.; Mungall, Andrew J.; Moore, Richard A.; Jabado, Nada; Bader, Gary D.; Jones, Steven J. M.; Malkin, David; Marra, Marco A.; Taylor, Michael D.


    The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon–driven, functional genomic mouse model of medulloblastoma with ‘humanized’ in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples (<5%). Whole-genome sequencing of 33 pairs of human diagnostic and post-therapy medulloblastomas demonstrated substantial genetic divergence of the dominant clone after therapy (<12% diagnostic events were retained at recurrence). In both mice and humans, the dominant clone at recurrence arose through clonal selection of a pre-existing minor clone present at diagnosis. Targeted therapy is unlikely to be effective in the absence of the target, therefore our results offer a simple, proximal, and remediable explanation for the failure of prior clinical trials of targeted therapy. PMID:26760213

  12. CPG-based Locomotion Controller Design for a Boxfish-like Robot

    Directory of Open Access Journals (Sweden)

    Wei Wang


    Full Text Available This paper focuses on a Central Pattern Generator (CPG-based locomotion controller design for a boxfish-like robot. The bio-inspired controller is aimed at flexible switching in multiple 3D swimming patterns and exact attitude control of yaw and roll such that the robot will swim more like a real boxfish. The CPG network comprises two layers, the lower layer is the network of coupled linear oscillators and the upper is the transition layer where the lower-dimensional locomotion stimuli are transformed into the higher-dimensional control parameters serving for all the oscillators. Based on such a two-layer framework, flexible switching between multiple three-dimensional swimming patterns, such as swimming forwards/backwards, turning left/right, swimming upwards/downwards and rolling clockwise/counter-clockwise, can be simply realized by inputting different stimuli. Moreover, the stability of the CPG network is strictly proved to guarantee the intrinsic stability of the swimming patterns. As to exact attitude control, based on this open-loop CPG network and the sensory feedback from the Inertial Measurement Unit (IMU, a closed-loop CPG controller is advanced for yaw and roll control of the robotic fish for the first time. This CPG-based online attitude control for a robotic fish will greatly facilitate high-level practical underwater applications. A series of relevant experiments with the robotic fish are conducted systematically to validate the effectiveness and stability of the open-loop and closed-loop CPG controllers.

  13. Aging of the microenvironment influences clonality in hematopoiesis.

    Directory of Open Access Journals (Sweden)

    Virag Vas

    Full Text Available The mechanisms of the age-associated exponential increase in the incidence of leukemia are not known in detail. Leukemia as well as aging are initiated and regulated in multi-factorial fashion by cell-intrinsic and extrinsic factors. The role of aging of the microenvironment for leukemia initiation/progression has not been investigated in great detail so far. Clonality in hematopoiesis is tightly linked to the initiation of leukemia. Based on a retroviral-insertion mutagenesis approach to generate primitive hematopoietic cells with an intrinsic potential for clonal expansion, we determined clonality of transduced hematopoietic progenitor cells (HPCs exposed to a young or aged microenvironment in vivo. While HPCs displayed primarily oligo-clonality within a young microenvironment, aged animals transplanted with identical pool of cells displayed reduced clonality within transduced HPCs. Our data show that an aged niche exerts a distinct selection pressure on dominant HPC-clones thus facilitating the transition to mono-clonality, which might be one underlying cause for the increased age-associated incidence of leukemia.


    Institute of Scientific and Technical Information of China (English)

    钱军; 薛永权; 虞斐; 吴亚芳; 潘金兰; 陆定伟


    Objective: To study the value of clonal analysis to the early diagnosis of myelodysplastic syndrome (MDS). Methods: Four types of clonal analyses were performed on the bone marrow samples from 50 patients suspected of MDS: (1) Conventional Cytogenetics (CC) for clonal chromosomal abnormalities; (2) BrdU-Sister Chromatid Differentiation (BrdU-SCD) for cell cycle kinetics; (3) Fluorescence in Situ Hybridization (FISH) for trisomy 8; (4) Polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) for N-ras mutation. Results: The diagnosis of forty-three patients was compatible with the FAB criteria for MDS. The other seven cases didn't meet the FAB criteria, with only one lineage of dyspoiesis or with no obvious dysplastic changes. Among these seven cases, two were morphologically diagnosed with suspicious refractory anemia, one with sideroblastic anemia, one with leukemoid reaction, one with hypercellular anemia and two with chronic aplastic anemia. Clonal analyses of the 7 patients showed that six cases had clonal karyotype abnormalities, four had prolonged cell cycle patterns, four had trisomy 8 of different proportions and one had mutation of the exon 1 of N-RAS. Thus, they were revaluated as MDS patients. Conclusion: The untypical MDS patients with one lineage dyspoiesis or without obvious dysplastic changes can be diagnosed early by combining multiple clonal analysis techniques such as CC, SCD, FISH and PCR-SSCR.

  15. Current perspectives on mitochondrial inheritance in fungi

    Directory of Open Access Journals (Sweden)

    Xu J


    Full Text Available Jianping Xu,1,2 He Li2 1Department of Biology, McMaster University, Hamilton, Canada; 2The Key Laboratory for Non-Wood Forest Cultivation and Conservation of the Federal Ministry of Education, Central South University of Forestry and Technology, Changsha, People’s Republic of China Abstract: The mitochondrion is an essential organelle of eukaryotes, generating the universal energy currency, adenosine triphosphate, through oxidative phosphorylation. However, aside from generation of adenosine triphosphate, mitochondria have also been found to impact a diversity of cellular functions and organ system health in humans and other eukaryotes. Thus, inheriting and maintaining functional mitochondria are essential for cell health. Due to the relative ease of conducting genetic and molecular biological experiments using fungi, they (especially the budding yeast Saccharomyces cerevisiae have been used as model organisms for investigating the patterns of inheritance and intracellular dynamics of mitochondria and mitochondrial DNA. Indeed, the diversity of mitochondrial inheritance patterns in fungi has contributed to our broad understanding of the genetic, cellular, and molecular controls of mitochondrial inheritance and their evolutionary implications. In this review, we briefly summarize the patterns of mitochondrial inheritance in fungi, describe the genes and processes involved in controlling uniparental mitochondrial DNA inheritance in sexual crosses in basidiomycete yeasts, and provide an overview of the molecular and cellular processes governing mitochondrial inheritance during asexual budding in S. cerevisiae. Together, these studies reveal that complex regulatory networks and molecular processes are involved in ensuring the transmission of healthy mitochondria to the progeny. Keywords: uniparental inheritance, biparental inheritance, mating type, actin cable, mitochore, mitochondrial partition 

  16. Testamental inheritance: Just a legal osmosis?

    Directory of Open Access Journals (Sweden)

    Đorđević-Crnobrnja Jadranka


    Full Text Available Bequeath, a dispose of personal property by the last will is an example of intervention of legislation within the complex of customary law. This influence is not unusual but certainly is less frequent than the influence of customary into civil law, especially so in their interaction within inheritance. This paper therefore tries to explain this example of legal osmosis in practice. In addition, the practice in testament inheritance shows also an influence of customary law into legislation. Hence, the paper will also try to discuss a relationship between customary and civil laws and succeeding problems in inheritance at the levels of individual and that of the society.

  17. A CpG oligonucleotide can protect mice from a low aerosol challenge dose of Burkholderia mallei. (United States)

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


    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.

  18. A CpG Oligonucleotide Can Protect Mice from a Low Aerosol Challenge Dose of Burkholderia mallei


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


    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-γ)-inducible protein 10, interleukin-12 (IL-12), IFN-γ, and IL-6. Preexposure therapy with CpG ODNs may protect victims of a biological attack from glanders.

  19. CpG Island Methylation in Human Lymphocytes Is Highly Correlated with DNA Sequence, Repeats, and Predicted DNA Structure


    Christoph Bock; Martina Paulsen; Sascha Tierling; Thomas Mikeska; Thomas Lengauer; Jörn Walter


    CpG island methylation plays an important role in epigenetic gene control during mammalian development and is frequently altered in disease situations such as cancer. The majority of CpG islands is normally unmethylated, but a sizeable fraction is prone to become methylated in various cell types and pathological situations. The goal of this study is to show that a computational epigenetics approach can discriminate between CpG islands that are prone to methylation from...

  20. The immune responses triggered by CpG ODNs in shrimp Litopenaeus vannamei are associated with LvTolls. (United States)

    Sun, Rui; Wang, Mengqiang; Wang, Lingling; Yue, Feng; Yi, Qilin; Huang, Mengmeng; Liu, Rui; Qiu, Limei; Song, Linsheng


    CpG oligodeoxynucleotides (ODNs) represent a kind of pathogen-associated molecular patterns (PAMPs) as well as a novel adjuvant that activate the innate immune system through interaction with Toll-like receptor 9 (TLR9) in mammals. In the present study, the synthetic oligodeoxynucleotides, CpG ODN 2395, was employed to investigate the interactive mode of CpG ODNs with three known Tolls (LvToll1-3) from shrimp Litopenaeus vannamei. The mature peptides of extracellular domains of LvTolls (LvToll-ECDs) were recombinant expressed and their binding activities to CpG ODN 2395 were further examined by ELISA. rLvToll1-ECD and rLvToll3-ECD exhibited affinity to CpG ODN 2395 in a dose-dependent manner when their concentrations ranged from 0.25 to 2.00 μmol/L, while rLvToll2-ECD did not show any binding activities to CpG ODN 2395 in tested concentrations. Additionally, after the stimulation of CpG ODN 2395, the luciferase activities of HEK293T cells transfected with LvToll1-mosaic or LvToll3-mosaic were significantly increased to 2.38-fold (pvannamei were indispensable for the triggering of immune responses by CpG ODNs, and the results provided a foundation for the application of CpG ODNs as the novel immunostimulants in aquaculture.

  1. Dose-effect relationship of CpG oligodeoxyribonucleotide 1826 in murine Lewis lung cancer treated with irradiation

    Directory of Open Access Journals (Sweden)

    Zhuang XB


    Full Text Available Xibing Zhuang,1 Tiankui Qiao,1 Sujuan Yuan,1 Wei Chen,1 Lin Zha,2 Li Yan11Department of Oncology, Jinshan Hospital, Medical Center of Fudan University, Shanghai, People's Republic of China; 2Department of Oncology, Tongling People's Hospital, Tongling, Anhui, People's Republic of ChinaBackground: Cytosine-phosphate-guanine (CpG oligodeoxyribonucleotides (ODNs, which induce signaling via Toll-like receptor 9, have recently been suggested to enhance sensitivity to traditional therapies, including chemotherapy, in certain cancer cell lines. This study aimed to define the dose-effect relationship for CpG ODN 1826 in increasing radiosensitivity and its impact on immune function in a mouse model of Lewis lung cancer.Methods: The tumor-bearing mouse model was induced by injecting Lewis lung cancer cells into the right anterior leg subcutaneously. Sixty-four C57BL/6 J mice were evenly randomized into eight groups, comprising: a control group; an irradiation group; a CpG ODN 0.15 group; a CpG ODN 0.3 group; a CpG ODN 0.45 group; a CpG 0.15 + irradiation group; a CpG 0.3 + irradiation group; and a CpG 0.45 + irradiation group. Tumor growth, serum tumor necrosis factor-alpha and interleukin-12 concentrations, spleen and thymus exponents, and effect of CpG on the secondary immune response were measured, and apoptosis of tumor cells was investigated using TdT-mediated dUTP nick end labeling (TUNEL after treatment.Results: Tumor volumes in the treated groups were smaller than in the control group, with those of the CpG 0.45 + irradiation group being the smallest. TUNEL showed that the apoptosis rate in all the active treatment groups was higher than in the control group. CpG ODN apoptosis rate, serum tumor necrosis factor-alpha and interleukin-12 levels, and the spleen and thymus exponent showed greater improvement in the groups receiving combination therapy of CpG ODN and irradiation than the control group or the group receiving irradiation alone. With the

  2. CpG Oligodeoxynucleotides Induce Differential Cytokine and Chemokine Gene Expression Profiles in Dapulian and Landrace Pigs


    Jiaqing Hu; Yongqing Zeng; Wei Chen; Hui Wang; Dandan Yang; Chuanhao Li


    Oligodeoxynucleotides containing unmethylated CpG motifs (CpG ODN) mimic the immunostimulatory activity of microbial DNA by interacting with Toll-like receptor 9 (TLR9) to activate both the innate and adaptive immune responses in different species. However, few studies have been published to compare the effects of CpG ODN on different pig breeds. Therefore, in this study, whole blood gene expression profiles of DPL and Landrace pigs treated with CpG ODN were studied using RNA-seq technology. ...

  3. 17beta-estradiol enhances the response of plasmacytoid dendritic cell to CpG.

    Directory of Open Access Journals (Sweden)

    Xiaoxi Li

    Full Text Available Gender differences in immune capabilities suggest that sex hormones such as estrogens were involved in the regulation of the immunocompetence. Numerous studies also suggest that plasmacytoid dendritic cells (PDCs play a pathogenic role in SLE. However, it is unclear whether estrogen can modulate the function of PDCs to influence the development of SLE. In the present study, PDCs from murine spleens were treated with 17beta-estradiol (E2 and CpG respectively or both in vitro, then cell viability, costimulatory molecule expression, cytokine secretion of PDCs, as well as stimulatory capacity of PDCs to B cells were analyzed. Results showed that E2 and CpG increased the cell viability and costimulatory molecule expression on PDCs synergistically. Moreover, the intracellular and extracellular secretion of IFN-alpha was increased by E2 or E2 plus CpG. In addition, E2 and CpG also increased the stimulatory capacity of PDCs to B cells, and the viability of B cells was decreased after neutralizing IFN-alpha significantly. In the experiments in vivo, mice received daily s.c. injections of E2 and CpG respectively or both, then we found that the plasma concentration of IgM were elevated by E2 and CpG synergistically and the expression of IFN-alpha/beta in spleens were noticeably increased by CpG plus E2 compared with the treatment of E2 or CpG only. This study indicates that E2 could exacerbate PDCs' activation with CpG, which further activates B cells to upregulate susceptibility to autoantigens. IFN-alpha plays an important role in the stimulatory effect of PDCs on B cells. E2 stimulation of IFN-alpha production may result in female prevalence in autoimmune diseases such as SLE through activation of PDCs. This study provides novel evidence of relationship between estrogen and SLE and also sheds light on gender biases among SLE patients.

  4. Hypermethylation of the CPG Island of p16 Gene Correlates with Gene Inactivation in Brain Glioma

    Institute of Scientific and Technical Information of China (English)

    JIAOBaohua; GENGShaomei; 等


    Objective:To study the correlation between hypermethylation of the CPG island of p16 gene and its inactivation in gliomas.Mehtods:In 50 cases of brain glioma,immunohistochemical method was applied to detect the expression of p16 protein; PCR a-nalysis was performed to identify the deletion of exons 1,2 of p16 gene and hypermethylation of CPG island of exon 1 of p16 gene in brain glioma.Results:Immunohistochemical analysis showed that p16 protein expression was negative in 27 cases(54%) and positive in 23 cases(46%) of 50 cases of brain gliomas.In the group with negative p16 protein expression(n=27 cases),RT-PCR analysis showed that there were 9 cases(33%) with homozygous deletions ofp16 gene and 7 cases(26%) with hypermethylation of CPG island of p16 gene.Conclusion:The transcriptional inhibition of p16 gene may be induced by aberrant hypermethylation of p16 gene 5'-CPG island in some of the cases without the homozygous deletions of p16 gene.Hypermethylation of 5'-CPG island is one of the important mechanisms for p16 gene inactivation.

  5. CpG methylation increases the DNA binding of 9-aminoacridine carboxamide Pt analogues. (United States)

    Kava, Hieronimus W; Murray, Vincent


    This study investigated the effect of CpG methylation on the DNA binding of cisplatin analogues with an attached aminoacridine intercalator. DNA-targeted 9-aminoacridine carboxamide Pt complexes are known to bind at 5'-CpG sequences. Their binding to methylated and non-methylated 5'-CpG sequences was determined and compared with cisplatin. The damage profiles of each platinum compound were quantified via a polymerase stop assay with fluorescently labelled primers and capillary electrophoresis. Methylation at 5'-CpG was shown to significantly increase the binding intensity for the 9-aminoacridine carboxamide compounds, whereas no significant increase was found for cisplatin. 5'-CpG methylation had the largest effect on the 9-ethanolamine-acridine carboxamide Pt complex, followed by the 9-aminoacridine carboxamide Pt complex and the 7-fluoro complex. The methylation state of a cell's genome is important in maintaining normal gene expression, and is often aberrantly altered in cancer cells. An analogue of cisplatin which differentially targets methylated DNA may be able to improve its therapeutic activity, or alter its range of targets and evade the chemoresistance which hampers cisplatin efficacy in clinical use.

  6. Nucleosome Positions and Differential Methylation Status of Various Regions within MLH1 CpG Island

    Institute of Scientific and Technical Information of China (English)

    BAI Hua; ZHOU Jing; DENG Da-jun


    Objective:To determine the relationship between nucleosome positions and formation of differential methylation of the reported region A,B,C,and D within the MLH1 CpG island. Methods:Methylation of the MLH1 promoter was analyzed by combined of bisulfite restriction assay.Chromatin of RKO and MGC803 cells were extracted and digested by Mnase.Mononucleosomal DNA fragment was isolated and used as templates for detection of nucleosomal distribution by a battery of quantitative PCRs covering the full MLH1 promoter region. Results:The MLH1 was methylated in RKO and unmethylated in MGC803.At the region B,where methylation of CpG sites did not correlated with transcription of this gene well,qPCR product of the M-3(-599nt~-475nt)fragment was amplified in both RKO and MGC803 cells.However,at the region C and D within the core promoter,where methylation of CpG sites correlated with loss of MLH1 transcription well,the M-7(-257nt~-153nt)and M-8(-189nt~-71nt)fragments were amplified remarkably only in RKO cells. Conclusion:Nucleosome may be the basic unit for both CpG methylation and methylation-related regulation of gene transcription.Methylation status of CpG sites within the same nucleosome may be homogeneous;between different nucleosomes,homogeneous or heterogeneous.

  7. Differential DNA Methylation Regions in Adult Human Sperm following Adolescent Chemotherapy: Potential for Epigenetic Inheritance (United States)

    Shnorhavorian, Margarett; Schwartz, Stephen M.; Stansfeld, Barbara; Sadler-Riggleman, Ingrid; Beck, Daniel


    Background The potential that adolescent chemotherapy can impact the epigenetic programming of the germ line to influence later life adult fertility and promote epigenetic inheritance was investigated. Previous studies have demonstrated a number of environmental exposures such as abnormal nutrition and toxicants can promote sperm epigenetic changes that impact offspring. Methods Adult males approximately ten years after pubertal exposure to chemotherapy were compared to adult males with no previous exposure. Sperm were collected to examine differential DNA methylation regions (DMRs) between the exposed and control populations. Gene associations and correlations to genetic mutations (copy number variation) were also investigated. Methods and Findings A signature of statistically significant DMRs was identified in the chemotherapy exposed male sperm. The DMRs, termed epimutations, were found in CpG desert regions of primarily 1 kilobase size. Observations indicate adolescent chemotherapy exposure can promote epigenetic alterations that persist in later life. Conclusions This is the first observation in humans that an early life chemical exposure can permanently reprogram the spermatogenic stem cell epigenome. The germline (i.e., sperm) epimutations identified suggest chemotherapy has the potential to promote epigenetic inheritance to the next generation. PMID:28146567

  8. Towards unifying inheritance and automatic program specialization

    DEFF Research Database (Denmark)

    Schultz, Ulrik Pagh


    Inheritance allows a class to be specialized and its attributes refined, but implementation specialization can only take place by overriding with manually implemented methods. Automatic program specialization can generate a specialized, effcient implementation. However, specialization of programs...... and specialization of classes (inheritance) are considered different abstractions. We present a new programming language, Lapis, that unifies inheritance and program specialization at the conceptual, syntactic, and semantic levels. This paper presents the initial development of Lapis, which uses inheritance...... with covariant specialization to control the automatic application of program specialization to class members. Lapis integrates object-oriented concepts, block structure, and techniques from automatic program specialization to provide both a language where object-oriented designs can be e#ciently implemented...

  9. Inheritance of fresh seed dormancy in groundnut

    African Journals Online (AJOL)



    Feb 19, 2008 ... The study showed that seed dormancy is controlled by monogenic inheritance with dormancy ..... Fertilizer Assoc Washington D. C.. John CM ... Dormancy release in Virginia-type peanut seeds by plant growth regulators.

  10. Inheritance and Synchronization in Concurrent OOP (United States)

    Briot, Jean-Pierre; Yonezawa, Akinori

    This paper discusses knowledge sharing (inheritance) mechanisms for Object-Oriented Programming (OOP) in the context of concurrent (distributed) languages. We review three different schemes: inheritance, delegation and copy. A fourth model, called recipe-query, is presented and all are compared and criticized. Techniques relying on the shared memory assumption are rejected. We point out the conflict between distributing knowledge among objects and the synchronization of concurrent objects.

  11. Asexual and sexual reproductive strategies in clonal plants

    Institute of Scientific and Technical Information of China (English)

    ZHANG Yufen; ZHANG Dayong


    Most plants can reproduce both sexually and asexually (or vegetatively),and the balance between the two reproductive modes may vary widely between and within species.Extensive clonal growth may affect the evolution of life history traits in many ways.First,in some clonal species,sexual reproduction and sex ratio vary largely among populations.Variation in sexual reproduction may strongly affect plant's adaptation to local environments and the evolution of the geographic range.Second,clonal growth can increase floral display,and thus pollinator attraction,while it may impose serious constraints and evolutionary challenges on plants through geitonogamy that may strongly influence pollen dispersal.Geitonogamous pollination can bring a cost to plant fitness through both female and male functions.Some co-evolutionary interactions,therefore,may exist between the spatial structure and the mating behavior of clonal plants.Finally,a trade-off may exist between sexual reproduction and clonal growth.Resource allocation to the two reproductive modes may depend on environmental conditions,competitive dominance,life span,and genetic factors.If different reproductive modes represent adaptive strategies for plants in different environments,we expect that most of the resources should be allocated to sexual reproduction in habitats with fluctuating environmental conditions and strong competition,while clonal growth should be dominant in stable habitats.Yet we know little about the consequence of natural selection on the two reproductive modes and factors which control the balance of the two reproductive modes.Future studies should investigate the reproductive strategies of clonal plants simultaneously from both sexual and asexual perspectives.

  12. CPG-inspired workspace trajectory generation and adaptive locomotion control for quadruped robots. (United States)

    Liu, Chengju; Chen, Qijun; Wang, Danwei


    This paper deals with the locomotion control of quadruped robots inspired by the biological concept of central pattern generator (CPG). A control architecture is proposed with a 3-D workspace trajectory generator and a motion engine. The workspace trajectory generator generates adaptive workspace trajectories based on CPGs, and the motion engine realizes joint motion imputes. The proposed architecture is able to generate adaptive workspace trajectories online by tuning the parameters of the CPG network to adapt to various terrains. With feedback information, a quadruped robot can walk through various terrains with adaptive joint control signals. A quadruped platform AIBO is used to validate the proposed locomotion control system. The experimental results confirm the effectiveness of the proposed control architecture. A comparison by experiments shows the superiority of the proposed method against the traditional CPG-joint-space control method.

  13. An invasive clonal plant benefits from clonal integration more than a co-occurring native plant in nutrient-patchy and competitive environments. (United States)

    You, Wenhua; Fan, Shufeng; Yu, Dan; Xie, Dong; Liu, Chunhua


    Many notorious invasive plants are clonal, however, little is known about the different roles of clonal integration effects between invasive and native plants. Here, we hypothesize that clonal integration affect growth, photosynthetic performance, biomass allocation and thus competitive ability of invasive and native clonal plants, and invasive clonal plants benefit from clonal integration more than co-occurring native plants in heterogeneous habitats. To test these hypotheses, two stoloniferous clonal plants, Alternanthera philoxeroides (invasive), Jussiaea repens (native) were studied in China. The apical parts of both species were grown either with or without neighboring vegetation and the basal parts without competitors were in nutrient- rich or -poor habitats, with stolon connections were either severed or kept intact. Competition significantly reduced growth and photosynthetic performance of the apical ramets in both species, but not the biomass of neighboring vegetation. Without competition, clonal integration greatly improved the growth and photosynthetic performance of both species, especially when the basal parts were in nutrient-rich habitats. When grown with neighboring vegetation, growth of J. repens and photosynthetic performance of both species were significantly enhanced by clonal integration with the basal parts in both nutrient-rich and -poor habitats, while growth and relative neighbor effect (RNE) of A. philoxeroides were greatly improved by clonal integration only when the basal parts were in nutrient-rich habitats. Moreover, clonal integration increased A. philoxeroides's biomass allocation to roots without competition, but decreased it with competition, especially when the basal ramets were in nutrient-rich sections. Effects of clonal integration on biomass allocation of J. repens was similar to that of A. philoxeroides but with less significance. These results supported our hypothesis that invasive clonal plants A. philoxeroides benefits

  14. Effect of the assignment of ancestral CpG state on the estimation of nucleotide substitution rates in mammals

    Directory of Open Access Journals (Sweden)

    Keightley Peter D


    Full Text Available Abstract Background Molecular evolutionary studies in mammals often estimate nucleotide substitution rates within and outside CpG dinucleotides separately. Frequently, in alignments of two sequences, the division of sites into CpG and non-CpG classes is based simply on the presence or absence of a CpG dinucleotide in either sequence, a procedure that we refer to as CpG/non-CpG assignment. Although it likely that this procedure is biased, it is generally assumed that the bias is negligible if species are very closely related. Results Using simulations of DNA sequence evolution we show that assignment of the ancestral CpG state based on the simple presence/absence of the CpG dinucleotide can seriously bias estimates of the substitution rate, because many true non-CpG changes are misassigned as CpG. Paradoxically, this bias is most severe between closely related species, because a minimum of two substitutions are required to misassign a true ancestral CpG site as non-CpG whereas only a single substitution is required to misassign a true ancestral non-CpG site as CpG in a two branch tree. We also show that CpG misassignment bias differentially affects fourfold degenerate and noncoding sites due to differences in base composition such that fourfold degenerate sites can appear to be evolving more slowly than noncoding sites. We demonstrate that the effects predicted by our simulations occur in a real evolutionary setting by comparing substitution rates estimated from human-chimp coding and intronic sequence using CpG/non-CpG assignment with estimates derived from a method that is largely free from bias. Conclusion Our study demonstrates that a common method of assigning sites into CpG and non CpG classes in pairwise alignments is seriously biased and recommends against the adoption of ad hoc methods of ancestral state assignment.

  15. Allogeneic hematopoietic stem cell transplantation for inherited bone marrow failure syndromes. (United States)

    Dalle, Jean-Hugues; Peffault de Latour, Régis


    Inherited bone marrow failure (IBMF) syndromes are a heterogeneous group of rare hematological disorders characterized by the impairment of hematopoiesis, which harbor specific clinical presentations and pathogenic mechanisms. Some of these syndromes may progress through clonal evolution, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Most prominent are failures of DNA repair such as Fanconi Anemia and much rarer failure of ribosomal apparatus, e.g., Diamond Blackfan Anemia or of telomere elongation such as dyskeratosis congenita. In these congenital disorders, hematopoietic stem cell transplantation (HSCT) is often a consideration. However, HSCT will not correct the underlying disease and possible co-existing extra-medullary (multi)-organ defects, but will improve BMF. Indications as well as transplantation characteristics are most of the time controversial in this setting because of the rarity of reported cases. The present paper proposes a short overview of current practices.

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

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


    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.

  17. CpG Methylation, a Parent-of-Origin Effect for Maternal-Biased Transmission of Congenital Myotonic Dystrophy. (United States)

    Barbé, Lise; Lanni, Stella; López-Castel, Arturo; Franck, Silvie; Spits, Claudia; Keymolen, Kathelijn; Seneca, Sara; Tomé, Stephanie; Miron, Ioana; Letourneau, Julie; Liang, Minggao; Choufani, Sanaa; Weksberg, Rosanna; Wilson, Michael D; Sedlacek, Zdenek; Gagnon, Cynthia; Musova, Zuzana; Chitayat, David; Shannon, Patrick; Mathieu, Jean; Sermon, Karen; Pearson, Christopher E


    CTG repeat expansions in DMPK cause myotonic dystrophy (DM1) with a continuum of severity and ages of onset. Congenital DM1 (CDM1), the most severe form, presents distinct clinical features, large expansions, and almost exclusive maternal transmission. The correlation between CDM1 and expansion size is not absolute, suggesting contributions of other factors. We determined CpG methylation flanking the CTG repeat in 79 blood samples from 20 CDM1-affected individuals; 21, 27, and 11 individuals with DM1 but not CDM1 (henceforth non-CDM1) with maternal, paternal, and unknown inheritance; and collections of maternally and paternally derived chorionic villus samples (7 CVSs) and human embryonic stem cells (4 hESCs). All but two CDM1-affected individuals showed high levels of methylation upstream and downstream of the repeat, greater than non-CDM1 individuals (p = 7.04958 × 10(-12)). Most non-CDM1 individuals were devoid of methylation, where one in six showed downstream methylation. Only two non-CDM1 individuals showed upstream methylation, and these were maternally derived childhood onset, suggesting a continuum of methylation with age of onset. Only maternally derived hESCs and CVSs showed upstream methylation. In contrast, paternally derived samples (27 blood samples, 3 CVSs, and 2 hESCs) never showed upstream methylation. CTG tract length did not strictly correlate with CDM1 or methylation. Thus, methylation patterns flanking the CTG repeat are stronger indicators of CDM1 than repeat size. Spermatogonia with upstream methylation may not survive due to methylation-induced reduced expression of the adjacent SIX5, thereby protecting DM1-affected fathers from having CDM1-affected children. Thus, DMPK methylation may account for the maternal bias for CDM1 transmission, larger maternal CTG expansions, age of onset, and clinical continuum, and may serve as a diagnostic indicator.

  18. TCRβ clonality improves diagnostic yield of TCRγ clonality in refractory celiac disease. (United States)

    Perfetti, Vittorio; Brunetti, Laura; Biagi, Federico; Ciccocioppo, Rachele; Bianchi, Paola I; Corazza, Gino R


    Refractory celiac disease (RCD) is a preneoplastic condition as many patients develop an enteropathy-type T-cell lymphoma, a mature T-cell receptor α-β lymphoma arising in the gut with an ominous outcome. Recently, research focused on a population of intraepithelial intestinal lymphocytes expressing the same lymphoma T-cell receptor variable region (V)γ, as shown by polymerase chain reaction (PCR) analysis and sequencing. Meanwhile, the Biomedicine and Health-2 Concerted Action has made available standardized, highly specific, and sensitive PCR assays not only for Vγ but also for Vβ. We verified whether analyzing both rearrangements in duodenal biopsies from RCD patients increases the diagnostic accuracy of this method. Duodenal biopsies were analyzed from 15 RCD patients, 21 negative controls, and 2 positive controls (enteropathy-type T-cell lymphoma complicating celiac disease). Multiplex clonality analyses were performed according to the Biomedicine and Health-2 protocols. PCR products were cloned and sequenced. Monoclonal rearrangements were found in 5/15 samples from patients with RCD (both rearrangements in 2 cases, Vβ only in 2, and only 1 solitary Vγ clonality). Monoclonality was found in 4/8 of the RCD patients who subsequently died, whereas only 1/7 of the patients still alive presented a monoclonal rearrangement. Positive controls revealed both monoclonal rearrangements; rearrangements were not detected in 20 of 21 negative controls. Sequencing of the amplified fragments confirmed the results. The combined analysis of both rearrangements allowed recognition of monoclonal populations in otherwise negative patients, with detection rates from 20% (Vγ only) to 33% (Vγ and Vβ), thus raising the likelihood of early identification of RCD patients at high risk of death.

  19. Specific siRNA Downregulated TLR9 and Altered Cytokine Expression Pattern in Macrophage after CpG DNA Stimulation

    Institute of Scientific and Technical Information of China (English)

    Bin Qiao; Baohua Li; Xiuli Yang; Hongyong Zhang; Yiwei Chu; Ying Wang; Sidong Xiong


    Bacterial CpG DNA or synthetic oligonucleotides (ODNs) that contain unmethylated CpG motifs (CpG ODN) can directly activate antigen-presenting cells (APCs) to secrete various cytokines through the intracellular receptor TLR9. Cytokine profiles elicited by the actions of stimulatory CpG DNA on TLR9 expressed APCs are crucial to the subsequent immune responses. To date, cytokine profiles in APCs upon CpG ODN stimulation in vitro are not fully investigated. In the present study, vector-based siRNA was used to downregulate TLR9 expression. Cytokine profiles were observed in murine macrophage cell line RAW264.7 transfected with TLR9-siRNA plasmid upon CpG ODN stimulation. We found that not all the cytokine expressions by the macrophage were decreased while TLR9 was downregulated. IL-12, TNF-α, IFN-γ and IL-1β expressions were significantly decreased, but IL-6,IFN-β and IL-10 expressions were not affected. Interestingly, the level of IFN-α was even increased. This alteration of cytokines produced by TLR9-downregulated APCs upon CpG ODN stimulation might indicate that the role of CpG DNA is more complicated in the pathogenesis and prevention of diseases. Cellular & Molecular Immunology.2005;2(2):130-135.

  20. Comparative Genomic Study Reveals a Transition from TA Richness in Invertebrates to GC Richness in Vertebrates at CpG Flanking Sites: An Indication for Context-Dependent Mutagenicity of Methylated CpG Sites

    Institute of Scientific and Technical Information of China (English)

    Yong Wang; Frederick C.C. Leung


    Vertebrate genomes are characterized with CpG deficiency, particularly for GC-poor regions. The GC content-related CpG deficiency is probably caused by context-dependent deamination of methylated CpG sites. This hypothesis was examined in this study by comparing nucleotide frequencies at CpG flanking positions among invertebrate and vertebrate genomes. The finding is a transition of nucleotide preference of 5' T to 5' A at the invertebrate-vertebrate boundary, indicating that a large number of CpG sites with 5' Ts were depleted because of global DNA methylation developed in vertebrates. At genome level, we investigated CpG observed/expected (obs/exp) values in 500 bp fragments, and found that higher CpG obs/exp value is shown in GC-poor regions of invertebrate genomes (except sea urchin) but in GC-rich sequences of vertebrate genomes. We next compared GC content at CpG flanking positions with genomic average, showing that the GC content is lower than the average in invertebrate genomes, but higher than that in vertebrate genomes. These results indicate that although 5' T and 5' A are different in inducing deamination of methylated CpG sites, GC content is even more important in affecting the deamination rate. In all the tests, the results of sea urchin are similar to vertebrates perhaps due to its fractional DNA methylation.CpG deficiency is therefore suggested to be mainly a result of high mutation rates of methylated CpG sites in GC-poor regions.

  1. Clonal Strategy Algorithm Based on the Immune Memory

    Institute of Scientific and Technical Information of China (English)

    Ruo-Chen Liu; Li-Cheng Jiao; Hai-Feng Du


    Based on the clonal selection theory and immune memory mechanism in the natural immune system, a novel artificial immune system algorithm, Clonal Strategy Algorithm based on the Immune Memory (CSAIM), is proposed in this paper. The algorithm realizes the evolution of antibody population and the evolution of memory unit at the same time, and by using clonal selection operator, the global optimal computation can be combined with the local searching. According to antibody-antibody (Ab-Ab) affinity and antibody-antigen (Ab-Ag) affinity, the algorithm can allot adaptively the scales of memory unit and antibody population. It is proved theoretically that CSAIM is convergent with probability 1. And with the computer simulations of eight benchmark functions and one instance of traveling salesman problem (TSP), it is shown that CSAIM has strong abilities in having high convergence speed, enhancing the diversity of the population and avoiding the premature convergence to some extent.

  2. Enumeration of Neural Stem Cells Using Clonal Assays. (United States)

    Narayanan, Gunaseelan; Yu, Yuan Hong; Tham, Muly; Gan, Hui Theng; Ramasamy, Srinivas; Sankaran, Shvetha; Hariharan, Srivats; Ahmed, Sohail


    Neural stem cells (NSCs) have the ability to self-renew and generate the three major neural lineages - astrocytes, neurons and oligodendrocytes. NSCs and neural progenitors (NPs) are commonly cultured in vitro as neurospheres. This protocol describes in detail how to determine the NSC frequency in a given cell population under clonal conditions. The protocol begins with the seeding of the cells at a density that allows for the generation of clonal neurospheres. The neurospheres are then transferred to chambered coverslips and differentiated under clonal conditions in conditioned medium, which maximizes the differentiation potential of the neurospheres. Finally, the NSC frequency is calculated based on neurosphere formation and multipotency capabilities. Utilities of this protocol include the evaluation of candidate NSC markers, purification of NSCs, and the ability to distinguish NSCs from NPs. This method takes 13 days to perform, which is much shorter than current methods to enumerate NSC frequency.

  3. Molecular autopsy in victims of inherited arrhythmias. (United States)

    Semsarian, Christopher; Ingles, Jodie


    Sudden cardiac death (SCD) is a rare but devastating complication of a number of underlying cardiovascular diseases. While coronary artery disease and acute myocardial infarction are the most common causes of SCD in older populations, inherited cardiac disorders comprise a substantial proportion of SCD cases aged less than 40 years. Inherited cardiac disorders include primary inherited arrhythmogenic disorders such as familial long QT syndrome (LQTS), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and inherited cardiomyopathies, most commonly hypertrophic cardiomyopathy (HCM). In up to 40% of young SCD victims (defined as 1-40 years old, excluding sudden unexplained death in infancy from 0 to 1 years, referred to as SIDS), no cause of death is identified at postmortem [so-called "autopsy negative" or "sudden arrhythmic death syndrome" (SADS)]. Management of families following a SCD includes the identification of the cause of death, based either on premorbid clinical details or the pathological findings at the postmortem. When no cause of death is identified, genetic testing of DNA extracted from postmortem tissue (the molecular autopsy) may identify a cause of death in up to 30% of SADS cases. Targeted clinical testing in a specialized multidisciplinary clinic in surviving family members combined with the results from genetic testing, provide the optimal setting for the identification of relatives who may be at risk of having the same inherited heart disease and are therefore also predisposed to an increased risk of SCD.

  4. Inheritance of telomere length in a bird.

    Directory of Open Access Journals (Sweden)

    Thorsten Horn

    Full Text Available Telomere dynamics are intensively studied in human ageing research and epidemiology, with many correlations reported between telomere length and age-related diseases, cancer and death. While telomere length is influenced by environmental factors there is also good evidence for a strong heritable component. In human, the mode of telomere length inheritance appears to be paternal and telomere length differs between sexes, with females having longer telomeres than males. Genetic factors, e.g. sex chromosomal inactivation, and non-genetic factors, e.g. antioxidant properties of oestrogen, have been suggested as possible explanations for these sex-specific telomere inheritance and telomere length differences. To test the influence of sex chromosomes on telomere length, we investigated inheritance and sex-specificity of telomere length in a bird species, the kakapo (Strigops habroptilus, in which females are the heterogametic sex (ZW and males are the homogametic (ZZ sex. We found that, contrary to findings in humans, telomere length was maternally inherited and also longer in males. These results argue against an effect of sex hormones on telomere length and suggest that factors associated with heterogamy may play a role in telomere inheritance and sex-specific differences in telomere length.

  5. Recessively inherited deficiencies predisposing to cancer. (United States)

    Müller, H


    The genetic factors involved in the multistep process of carcinogenesis can be divided at least into two major categories: 1. Mutated or lost genes, which may directly represent one step in the sequential process (tumour suppressor genes); inheritance of one tumour suppressor gene causes dominant expression of the carcinogenic phenotype (the dominant inheritance is described in the accompanying paper); 2. Other genes, which lead to conditions that favour the development of cancer and generally are inherited in a recessive fashion; they are the subject of this paper. Autosomal recessively inherited diseases, such as xeroderma pigmentosum, ataxia-telangiectasia, Bloom's syndrome and Fanconi's anaemia display increased genome instability (chromosomal fragility and/or DNA-repair deficiencies) and are associated in the homozygote and probably also in the heterozygote state with defined malignancies. Neoplasms particularly of the lymphoreticular system frequently occur in patients with genetically determined immunodeficiencies (e.g. severe combined immune deficiency or Wiskott-Aldrich syndrome). People differ due to their individual genetic constitution in their responses to various classes of carcinogens such as physical and chemical agents, to dietary habits, as well as to viruses. Furthermore, tumours are often found in patients displaying premature aging (e.g. Werner's syndrome). In addition, several metabolic abnormalities such as genetic syndromes featuring chronic liver disease, but also many other inherited metabolic conditions have cancer as a regular or frequent complication.

  6. [Genetic diagnostic testing in inherited retinal dystrophies]. (United States)

    Kohl, S; Biskup, S


    Inherited retinal dystrophies are clinically and genetically highly heterogeneous. They can be divided according to the clinical phenotype and course of the disease, as well as the underlying mode of inheritance. Isolated retinal dystrophies (i.e., retinitis pigmentosa, Leber's congenital amaurosis, cone and cone-rod dystrophy, macular dystrophy, achromatopsia, congenital stationary nightblindness) and syndromal forms (i.e., Usher syndrome, Bardet-Biedl syndrome) can be differentiated. To date almost 180 genes and thousands of distinct mutations have been identified that are responsible for the different forms of these blinding illnesses. Until recently, there was no adequate diagnostic genetic testing available. With the development of the next generation sequencing technologies, a comprehensive genetic screening analysis for all known genes for inherited retinal dystrophies has been established at reasonable costs and in appropriate turn-around times. Depending on the primary clinical diagnosis and the presumed mode of inheritance, different diagnostic panels can be chosen for genetic testing. Statistics show that in 55-80 % of the cases the genetic defect of the inherited retinal dystrophy can be identified with this approach, depending on the initial clinical diagnosis. The aim of any genetic diagnostics is to define the genetic cause of a given illness within the affected patient and family and thereby i) confirm the clinical diagnosis, ii) provide targeted genetic testing in family members, iii) enable therapeutic intervention, iv) give a prognosis on disease course and progression and v) in the long run provide the basis for novel therapeutic approaches and personalised medicine.

  7. Clonal evolution and therapeutic resistance in solid tumors

    Directory of Open Access Journals (Sweden)

    Elizabeth eLenkiewicz


    Full Text Available Tumors frequently arise as a result of an acquired genomic instability and the subsequent evolution of neoplastic populations with variable genomes. A barrier to the study of the somatic genetics of human solid tumors in vivo is the presence of admixtures of non-neoplastic cells with normal genomes in patient samples. These can obscure the presence of somatic aberrations including mutations, homozygous deletions, and breakpoints in biopsies of interest. Furthermore, clinical samples frequently contain multiple neoplastic populations that cannot be distinguished by morphology. Consequently, it is difficult to determine whether mutations detected in a sample of interest are concurrent in a single clonal population or if they occur in distinct cell populations in the same sample. The advent of targeted therapies increases the selection for preexisting populations. However the asymmetric distribution of therapeutic targets in clonal populations provides a mechanism for the rapid evolution of resistant disease. Thus, there is a need to not only isolate tumor from normal cells, but to also enrich distinct populations of clonal neoplastic cells in order to apply genome technologies to identify clinically relevant genomic aberrations that drive disease in patients in vivo. To address this we have applied single and multiparameter DNA content based flow assays to the study of solid tumors. Our work has identified examples of clonal resistance to effective therapies. This includes androgen withdrawal in advanced prostate cancer. In addition we demonstrate examples of co-existing clonal populations with highly aberrant genomes and ploidies in a wide variety of solid tumors. We propose that clonal analysis of tumors, based on flow cytometry and high resolution genome analyses of purified neoplastic populations, provides a unique approach to the study of therapeutic responses and the evolution of resistance.

  8. Dynamic evolution of clonal epialleles revealed by methclone. (United States)

    Li, Sheng; Garrett-Bakelman, Francine; Perl, Alexander E; Luger, Selina M; Zhang, Chao; To, Bik L; Lewis, Ian D; Brown, Anna L; D'Andrea, Richard J; Ross, M Elizabeth; Levine, Ross; Carroll, Martin; Melnick, Ari; Mason, Christopher E


    We describe methclone, a novel method to identify epigenetic loci that harbor large changes in the clonality of their epialleles (epigenetic alleles). Methclone efficiently analyzes genome-wide DNA methylation sequencing data. We quantify the changes using a composition entropy difference calculation and also introduce a new measure of global clonality shift, loci with epiallele shift per million loci covered, which enables comparisons between different samples to gauge overall epiallelic dynamics. Finally, we demonstrate the utility of methclone in capturing functional epiallele shifts in leukemia patients from diagnosis to relapse. Methclone is open-source and freely available at

  9. [Clonality lymphoid study through rearrangement analysis of antigen receptor]. (United States)

    Villamizar-Rivera, Nicolás; Olaya, Natalia


    As a rule, malignant lymphoid proliferations are clonal. While most of the time the biological potential can be established through routine pathologic examination and auxiliary techniques, some cases are difficult to classify. Moreover, there are situations in which there are dominant clones whose analysis are important, such as occur in autoimmune diseases and immunodeficiency. This paper presents in an understandable way the main techniques for the study of clonality in lymphoid lesions, i.e. the analysis of rearrangements of antigen receptor genes by multiplex polymerase chain reaction (PCR) based tests.

  10. Interferon-α/β receptor-mediated selective induction of a gene cluster by CpG oligodeoxynucleotide 2006

    Directory of Open Access Journals (Sweden)

    Wakiguchi Hiroshi


    Full Text Available Abstract Background Oligodeoxynucleotides containing unmethylated CpG motifs (CpG ODN are known to exert a strong adjuvant effect on Th1 immune responses. Although several genes have been reported, no comprehensive study of the gene expression profiles in human cells after stimulation with CpG ODN has been reported. Results This study was designed to identify a CpG-inducible gene cluster that potentially predicts for the molecular mechanisms of clinical efficacy of CpG ODN, by determining mRNA expression in human PBMC after stimulation with CpG ODN. PBMCs were obtained from the peripheral blood of healthy volunteers and cultured in the presence or absence of CpG ODN 2006 for up to 24 hours. The mRNA expression profile was evaluated using a high-density oligonucleotide probe array, GeneChip®. Using hierarchical clustering-analysis, out of a total of 10,000 genes we identified a cluster containing 77 genes as having been up-regulated by CpG ODN. This cluster was further divided into two sub-clusters by means of time-kinetics. (1 Inflammatory cytokines such as IL-6 and GM-CSF were up-regulated predominantly 3 to 6 hours after stimulation with CpG ODN, presumably through activation of a transcription factor, NF-κB. (2 Interferon (IFN-inducible anti-viral proteins, including IFIT1, OAS1 and Mx1, and Th1 chemoattractant IP-10, were up-regulated predominantly 6 to 24 hours after stimulation. Blocking with mAb against IFN-α/β receptor strongly inhibited the induction of these IFN-inducible genes by CpG ODN. Conclusion This study provides new information regarding the possible immunomodulatory effects of CpG ODN in vivo via an IFN-α/β receptor-mediated paracrine pathway.

  11. Maternal inheritance of mitochondria in Eucalyptus globulus. (United States)

    Vaillancourt, R E; Petty, A; McKinnon, G E


    It is important to verify mitochondrial inheritance in plant species in which mitochondrial DNA (mtDNA) will be used as a source of molecular markers. We used a polymerase chain reaction (PCR)/restriction fragment length polymorphism (RFLP) approach to amplify mitochondrial introns from subunits 1, 4, 5, and 7 of NADH dehydrogenase (nad) and cytochrome oxidase subunit II (cox2) in Eucalyptus globulus. PCR fragments were then either sequenced or cut with restriction enzymes to reveal polymorphism. Sequencing cox2 showed that eucalypts lack the intron between exons 1 and 2. One polymorphism was found in intron 2-3 of nad7 following restriction digests with HphI. Fifty-four F1 progeny from seven families with parents distinguishable in their mitochondrial nad7 were screened to show that mitochondria were maternally inherited in E. globulus. These results constitute the first report of mitochondrial inheritance in the family Myrtaceae.

  12. Inherited cardiomyopathies mimicking arrhythmogenic right ventricular cardiomyopathy. (United States)

    Roberts, Jason D; Veinot, John P; Rutberg, Julie; Gollob, Michael H


    Arrhythmogenic right ventricular cardiomyopathy (ARVC) represents an inherited cardiomyopathy that manifests clinically with malignant ventricular arrhythmias, sudden cardiac death, and less commonly heart failure. The condition is characterized by replacement of the myocardium, primarily of the right ventricle, with fibrofatty tissue. Extensive fibrofatty replacement of the myocardium has been previously thought to be pathognomonic of ARVC; however, this report details two other forms of inherited cardiomyopathy, namely hypertrophic cardiomyopathy (HCM) and the PRKAG2 cardiac syndrome, that were found to have significant fibrofatty myocardial replacement at pathologic examination. This report represents the first documentation of inherited cardiomyopathies mimicking ARVC and highlights the concept that other cardiac conditions can be associated with fibrofatty replacement of the myocardium. Copyright 2010 Elsevier Inc. All rights reserved.

  13. Inherited Causes of Exocrine Pancreatic Dysfunction

    Directory of Open Access Journals (Sweden)

    Peter R Durie


    Full Text Available The exocrine pancreas is functionally immature at birth. Protease function is probably adequate, but lipase activity approximates 5% to 10% of adult values in the newborn and remains low in infancy. Pancreatic amylase secretion is essentially absent at birth and remains low through the first years of life. Functional disturbances of the exocrine pancreas are less frequent in childhood than in adult life. Causes of pancreatic dysfunction in childhood can be divided in two general categories: hereditary conditions, which directly affect the pancreas; and acquired disorders, in which loss of pancreatic function is a secondary phenomenon. Most inherited causes of pancreatic dysfunction are due to a generalized disorder. Cystic fibrosis is, by far, the most common inherited cause of disturbed pancreatic function among Caucasian children. All other inherited causes of exocrine pancreatic dysfunction (eg, Johanson-Blizzard syndrome are uncommon or rare.

  14. Transgenerational epigenetic inheritance: an open discussion. (United States)

    Nagy, Corina; Turecki, Gustavo


    Much controversy surrounds the idea of transgenerational epigenetics. Recent papers argue that epigenetic marks acquired through experience are passed to offspring, but as in much of the field of epigenetics, there is lack of precision in the definitions and perhaps too much eagerness to translate animal research to humans. Here, we review operational definitions of transgenerational inheritance and the processes of epigenetic programing during early development. Subsequently, based on this background, we critically examine some recent findings of studies investigating transgenerational inheritance. Finally, we discuss possible mechanisms that may explain transgenerational inheritance, including transmission of an epigenetic blueprint, which may predispose offspring to specific epigenetic patterning. Taken together, we conclude that presently, the evidence suggesting that acquired epigenetic marks are passed to the subsequent generation remains limited.

  15. On the role of sensory feedbacks in Rowat-Selverston CPG to improve robot legged locomotion

    Directory of Open Access Journals (Sweden)

    Elmira eAmrollah


    Full Text Available This paper presents the use of Rowat and Selverston-type of CPG to control locomotion. It focuses on the role of afferent exteroceptive and proprioceptive signals in the dynamic phase synchronization in CPG legged robots. The sensori-motor neural network architecture is evaluated to control a two-joint planar robot leg that slips on a rail. Then, the closed loop between the CPG and the mechanical system allows to study the modulation of rhythmic patterns and the effect of the sensing loop via sensory neurons during the locomotion task. Firstly simulations show that the proposed architecture easily allows to modulate rhythmic patterns of the leg, and therefore the velocity of the robot. Secondly, simulations show that sensori-feedbacks from foot/ground contact of the leg make the hip velocity smoother and larger. The results show that the Rowat-Selverston-type CPG with sensory feedbacks is an effective choice for building adaptive Neural Central Pattern Generators for legged robots.

  16. 75 FR 13555 - Compliance Policy Guide Sec. 540.375 Canned Salmon - Adulteration Involving Decomposition (CPG... (United States)


    ... FDA staff relating to decomposition in fish and fishery products, including canned salmon, is provided.... 540.375 Canned Salmon -- Adulteration Involving Decomposition (CPG 7108.10); Withdrawal of Guidance... Administration (FDA) is announcing the withdrawal of Compliance Policy Guide Sec. 540.375 Canned...

  17. Promoter CpG island hypermethylation in the development of cutaneous melanoma

    NARCIS (Netherlands)

    Gao, Linda


    Epigenetic mechanisms such as promoter methylation affect gene expression by inducing changes in organizational structure of chromatin rather than in the DNA sequence. Increased methylation of cytosine within cystosine-guanine (CpG) dinucleotides that are located at higher density in gene promoter r

  18. Promoter CpG island hypermethylation in the development of cutaneous melanoma

    NARCIS (Netherlands)

    Gao, Linda


    Epigenetic mechanisms such as promoter methylation affect gene expression by inducing changes in organizational structure of chromatin rather than in the DNA sequence. Increased methylation of cytosine within cystosine-guanine (CpG) dinucleotides that are located at higher density in gene promoter

  19. Reporter Gene Silencing in Targeted Mouse Mutants Is Associated with Promoter CpG Island Methylation. (United States)

    Kirov, Julia V; Adkisson, Michael; Nava, A J; Cipollone, Andreana; Willis, Brandon; Engelhard, Eric K; Lloyd, K C Kent; de Jong, Pieter; West, David B


    Targeted mutations in mouse disrupt local chromatin structure and may lead to unanticipated local effects. We evaluated targeted gene promoter silencing in a group of six mutants carrying the tm1a Knockout Mouse Project allele containing both a LacZ reporter gene driven by the native promoter and a neo selection cassette. Messenger RNA levels of the reporter gene and targeted gene were assessed by qRT-PCR, and methylation of the promoter CpG islands and LacZ coding sequence were evaluated by sequencing of bisulfite-treated DNA. Mutants were stratified by LacZ staining into presumed Silenced and Expressed reporter genes. Silenced mutants had reduced relative quantities LacZ mRNA and greater CpG Island methylation compared with the Expressed mutant group. Within the silenced group, LacZ coding sequence methylation was significantly and positively correlated with CpG Island methylation, while promoter CpG methylation was only weakly correlated with LacZ gene mRNA. The results support the conclusion that there is promoter silencing in a subset of mutants carrying the tm1a allele. The features of targeted genes which promote local silencing when targeted remain unknown.

  20. Aberrant development and plasticity of excitatory visual cortical networks in the absence of cpg15. (United States)

    Picard, Nathalie; Leslie, Jennifer H; Trowbridge, Sara K; Subramanian, Jaichandar; Nedivi, Elly; Fagiolini, Michela


    During development, experience plays a crucial role in sculpting neuronal connections. Patterned neural activity guides formation of functional neural circuits through the selective stabilization of some synapses and the pruning of others. Activity-regulated factors are fundamental to this process, but their roles in synapse stabilization and maturation is still poorly understood. CPG15, encoded by the activity-regulated gene candidate plasticity gene 15, is a small, glycosylphosphatidylinositol (GPI)-linked, extracellular protein that promotes synapse stabilization. Here we show that global knock-out of cpg15 results in abnormal postnatal development of the excitatory network in visual cortex and an associated disruption in development of visual receptive field properties. In addition, whereas repeated stimulation induced potentiation and depression in wild-type mice, the depression was slower in cpg15 knock-out mice, suggesting impairment in short-term depression-like mechanisms. These findings establish the requirement for cpg15 in activity-dependent development of the visual system and demonstrate the importance of timely excitatory network development for normal visual function.

  1. Biodistribution and metabolism of immunostimulatory oligodeoxynucleotide CPG 7909 in mouse and rat tissues following subcutaneous administration. (United States)

    Noll, Bernhard O; McCluskie, Michael J; Sniatala, Tanja; Lohner, Angela; Yuill, Stephanie; Krieg, Arthur M; Schetter, Christian; Davis, Heather L; Uhlmann, Eugen


    To evaluate pharmacokinetics (PK) and biodistribution, CPG 7909, a 24-mer immunostimulatory fully phosphorothioated oligodeoxynucleotide (PS-ODN), was administered by subcutaneous injection at 2, 5 and 12.5mg/kg to mice and at 9mg/kg to rats. Parent compound and metabolites were isolated from plasma and tissues and quantified by capillary gel electrophoresis with UV detection (CGE-UV) and molecular masses were determined by matrix-assisted-laser-desorption-ionization time of flight detection (MALDI-TOF). An established method for PS-ODN isolation from plasma and tissue was modified to prevent oxidation of the phosphorothioate bonds during the extraction process, significantly increasing sensitivity in the subsequent MALDI-TOF analysis. Concentrations of CPG 7909 and metabolites were highest at the injection site (>600mg/kg at 4h). Maximal concentrations in local (draining) lymph nodes (LLN), kidney and liver were 10-15% of that at the injection site. The highest total amount of PS-ODN (percentage of administered dose) was found in the liver (32% at 4h), followed closely by the injection site (23% at 4h). Only very low levels of CPG 7909 and metabolites were found in plasma and only during the first hours. Metabolites identified by MALDI-TOF were similar for both species and all analyzed tissues, although the relative amounts of the different metabolites varied with tissue and over time. Degradation of CPG 7909 in vivo occurred predominantly by 3'exonucleases with additional cleavage by endonucleases.

  2. CPG-based Sensory Feedback Control for Bio-inspired Multimodal Swimming

    Directory of Open Access Journals (Sweden)

    Ming Wang


    Full Text Available Sensory feedback plays a very significant role in the generation of diverse and stable movements for animals. In this paper we describe our effort to develop a Central Pattern Generator (CPG-based sensory feedback control for the creation of multimodal swimming for a multi-articulated robotic fish in the context of neurocomputing. The proposed control strategy is composed of two phases: the upper decision-making and the automatic adjustment. According to the upper control commands and the sensory inputs, different swimming gaits are determined by a finite state machine algorithm. At the same time, the sensory feedback is exploited to shape the CPG coupling forms and control parameters. In the automatic adjustment phase, the CPG model with sensory feedback will adapt the environment autonomously. Simulation and underwater tests are further conducted to verify the presented control scheme. It is found that the CPG-based sensory feedback control method can effectively improve the manoeuvrability and adaptability of the robotic fish in water.

  3. Proposed multigenic Composite Inheritance in major depression. (United States)

    Raymer, Katherine A; Waters, Robert F; Price, Catherine R


    Various rationale have been considered in the familial inheritance pattern of major depression ranging from simple one-gene Mendelian inheritance to pseudo-additive gene action. We instead predict broad genetic expressivity patterns in the progeny of parents where at least one parent has recurrent major depression. In keeping with this idea, we feel that recurrent major depression could involve an expression imbalance of "normal" genes either exclusively or along with allelic variation(s). The patterns of pathology are theoretically conceptualized as qualitative and quantitative, meaning that expressivity of the genetic pattern in these children may range from minimal to complete even among siblings. Thus, prediction of the particular genetic pattern expressed by a particular child might prove difficult. The complex inheritance pattern that we propose is referred to as Composite Inheritance. Composite Inheritance considers that both the up- and down-regulation of luxury genes and housekeeping genes are involved in this dichotomous qualitative inheritance pattern and also the wide quantitative expressivity. The luxury genes include such genes as those coding for the neurotransmitter transporters and receptors. The housekeeping genes found to date include those that code for proteins involved in gene transcription, secondary signaling systems, fatty acid metabolism and transport, and intracellular calcium homeostasis. Other luxury and housekeeping genes no doubt remain to be discovered. Our current research utilizes an empirical approach involving advanced genomics and specialized pattern recognition mathematics in families having at least one parent with recurrent major depression. The goal of our research is to develop a pattern recognition system of genetic expressivity in major depression to which prevention and early intervention may be tailored.

  4. Metalaxyl Resistance in Phytophthora infestans: Assessing Role of RPA190 Gene and Diversity Within Clonal Lineages. (United States)

    Matson, Michael E H; Small, Ian M; Fry, William E; Judelson, Howard S


    Prior work has shown that the inheritance of resistance to metalaxyl, an oomycete-specific fungicide, is complex and may involve multiple genes. Recent research indicated that a single nucleotide polymorphism (SNP) in the gene encoding RPA190, the largest subunit of RNA polymerase I, confers resistance to metalaxyl (or mefenoxam) in some isolates of the potato late blight pathogen Phytophthora infestans. Using both DNA sequencing and high resolution melt assays for distinguishing RPA190 alleles, we show here that the SNP is absent from certain resistant isolates of P. infestans from North America, Europe, and Mexico. The SNP is present in some members of the US-23 and US-24 clonal lineages, but these tend to be fairly sensitive to the fungicide based on artificial media and field test data. Diversity in the level of sensitivity, RPA190 genotype, and RPA190 copy number was observed in these lineages but were uncorrelated. Controlled laboratory crosses demonstrated that RPA190 did not cosegregate with metalaxyl resistance from a Mexican and British isolate. We conclude that while metalaxyl may be used to control many contemporary strains of P. infestans, an assay based on RPA190 will not be sufficient to diagnose the sensitivity levels of isolates.

  5. A Novel Chitosan CpG Nanoparticle Regulates Cellular and Humoral Immunity of Mice

    Institute of Scientific and Technical Information of China (English)


    To develop a safe and novel immunoadjuvant to enhance the immunity and resistance of animals against E.coli infection. Methods An 88-base immunostimulatory oligodeoxynuleotide containing eleven CpG motifs (CpG ODN)was synthesized and amplified by PCR. The chitosan nanoparticle (CNP) was prepared by ion linking method to entrap the CpG ODN that significantly promotes the proliferation of lymphocytes of pig in vitro. Then the CpG- CNP was inoculated into 21-day old Kunming mice, which were orally challenged with virulent K88/K99 E. Coli 35 days after inoculation. Blood was collected from the tail vein of mice on days 0, 7, 14, 21, 28, 35, 42, and 49 after inoculation to detect the changes and content of immunoglobulins, cytokines and immune cells by ELISA, such as IgG, IgA, IgM, IL-2, IL-4, and IL-6. Results The CpG provoked remarkable proliferation of lymphocytes of pig in vitro in comparison with that of control group (P<0.05). The inoculation with CpG-CNP significantly raised the content of IgG, IgM, and IgA in the sera of immunized mice (P<0.05). The levels of IL-2, IL-4, and IL-6 in the mice significantly increased in comparison with those in controls (P<0.05), so was the number of white blood cells and lymphocytes in immunized mice. The humoral and cellular immunities were significantly enhanced in immunized mice, which resisted the infection of E. coli and survived, while the control mice manifested evident symptoms and lesions of infection. Conclusions CpG-CNP can significantly promote cellular and humoral immunity and resistance of mice against E. coli infection, and can be utilized as an effective adjuvant to improve the immunoprotection and resistance of porcine against infectious disease.

  6. Doubly uniparental inheritance: two mitochondrial genomes, one precious model for organelle DNA inheritance and evolution. (United States)

    Passamonti, Marco; Ghiselli, Fabrizio


    Eukaryotes have exploited several mechanisms for organelle uniparental inheritance, so this feature arose and evolved independently many times in their history. Metazoans' mitochondria commonly experience strict maternal inheritance; that is, they are only transmitted by females. However, the most noteworthy exception comes from some bivalve mollusks, in which two mitochondrial lineages (together with their genomes) are inherited: one through females (F) and the other through males (M). M and F genomes show up to 30% sequence divergence. This inheritance mechanism is known as doubly uniparental inheritance (DUI), because both sexes inherit uniparentally their mitochondria. Here, we review what we know about this unusual system, and we propose a model for evolution of DUI that might account for its origin as sex determination mechanism. Moreover, we propose DUI as a choice model to address many aspects that should be of interest to a wide range of biological subfields, such as mitochondrial inheritance, mtDNA evolution and recombination, genomic conflicts, evolution of sex, and developmental biology. Actually, as research proceeds, mitochondria appear to have acquired a central role in many fundamental processes of life, which are not only in their metabolic activity as cellular power plants, such as cell signaling, fertilization, development, differentiation, ageing, apoptosis, and sex determination. A function of mitochondria in the origin and maintenance of sex has been also proposed.

  7. Paternal inheritance of mitochondrial DNA in the sheep (Ovine aries)

    Institute of Scientific and Technical Information of China (English)

    ZHAO; Xingbo


    fertilization of honeybee (Apis mellifera L.) eggs, Curr. Genet., 1993, 24(6): 539-543.[13]Sutherland, B., Stewart, D., Kenchington, E. R. et al., The fate of paternal mitochondrial DNA in developing female mus-sels, Mytilus edulis: implications for the mechanism of doubly uniparental inheritance of mitochondrial DNA, Genetics, 1998, 148(1): 341-347.[14]Hiendleder, S., Lewalski, H., Wassmuth, R. et al., The complete mitochondrial DNA sequence of the domestic sheep (Ovis aries) and comparison with the other major ovine haplotype, J. Mol. Evol., 1998, 47(4): 441-448.[15]Zardoya, R., Villalta, M., Lopez-Perez, M.J. et al., Nucleotide sequence of the sheep mitochondrial DNA D-loop and its flanking tRNA genes, Curr. Genet., 1995, 28(1): 94-96.[16]Caetano-Anolles, G., Gresshoff, P. M., Staining nucleic acids with silver, Promega Notes, 1994, 45, 15-18.[17]Cummins, J. M., Wakayama, T., Yanagimachi, R. et al., Fate of microinjected spermatid mitochondria in the mouse oocyte and embryo, Zygote, 1998, 6(3): 213-222.[18]Lopez, J. V., Yuhki, N., Masuda, R. et al., Numt, a recent transfer and tandem amplification of mitochondrial DNA to the nuclear genome of the domestic cat, J. Mol. Evol., 1994, 39: 174-190.[19]Wallace, D. C., Stugard, C., Murdock, D. et al., Ancient mtDNA sequences in the human nuclear genome: A potential source of errors in identifying pathogenic mutations, Proc. Natl. Acad. Sci. USA, 1997, 94: 14900-14905.[20]Eyre-Walker, A., Smith, N. H., Smith, J. M., How clonal are human mitochondria? Proc. R. Soc. Lond. B Biol. Sci., 1999, 266(1418): 477-483.[21]Hagelberg, E., Goldman, N., Lin, P. et al., Evidence for mitochondrial DNA recombination in a human population of is-land Melanesia, Proc. R. Soc. Lond. B Biol. Sci., 1999, 266(1418): 485-492.[22]Awadalla, P., Eyre-Walker, A., Smith, J. M., Linkage disequilibrium and recombination in Hominid mitochondrial DNA, Science, 1999, 286(5449): 2524-2525.

  8. Multiobjective optimization using an immunodominance and clonal selection inspired algorithm

    Institute of Scientific and Technical Information of China (English)

    GONG MaoGuo; JIAO LiCheng; MA WenPing; DU HaiFeng


    Based on the mechanisms of immunodominance and clonal selection theory, we propose a new multiobjective optimization algorithm, immune dominance clonal multiobjective algorithm (IDCMA). IDCMA is unique in that its fitness values of current dominated individuals are assigned as the values of a custom distance measure, termed as Ab-Ab affinity, between the dominated individuals and one of the nondominated individuals found so far. According to the values of Ab-Ab affin-ity, all dominated individuals (antibodies) are divided into two kinds, subdominant antibodies and cryptic antibodies. Moreover, local search only applies to the sub-dominant antibodies, while the cryptic antibodies are redundant and have no func-tion during local search, but they can become subdominant (active) antibodies during the subsequent evolution. Furthermore, a new immune operation, clonal proliferation is provided to enhance local search. Using the clonal proliferation operation, IDCMA reproduces individuals and selects their improved maturated progenies after local search, so single individuals can exploit their surrounding space effectively and the newcomers yield a broader exploration of the search space. The performance comparison of IDCMA with MISA, NSGA-II, SPEA, PAES, NSGA, VEGA, NPGA, and HLGA in solving six well-known multiobjective function optimization problems and nine multiobjective 0/1 knapsack problems shows that IDCMA has a good performance in converging to approximate Pareto-optimal fronts with a good distribution.

  9. New clonal strain of Candida auris, Delhi, India. (United States)

    Chowdhary, Anuradha; Sharma, Cheshta; Duggal, Shalini; Agarwal, Kshitij; Prakash, Anupam; Singh, Pradeep Kumar; Jain, Sarika; Kathuria, Shallu; Randhawa, Harbans S; Hagen, Ferry; Meis, Jacques F


    A new clonal strain of Candida auris is an emerging etiologic agent of fungemia in Delhi, India. In 12 patients in 2 hospitals, it was resistant to fluconazole and genotypically distinct from isolates from South Korea and Japan, as revealed by M13 and amplified fragment length polymorphism typing.

  10. New clonal strain of Candida auris, Delhi, India.



    A new clonal strain of Candida auris is an emerging etiologic agent of fungemia in Delhi, India. In 12 patients in 2 hospitals, it was resistant to fluconazole and genotypically distinct from isolates from South Korea and Japan, as revealed by M13 and amplified fragment length polymorphism typing.

  11. Clonal evolution in cancer: a tale of twisted twines. (United States)

    Janiszewska, Michalina; Polyak, Kornelia


    Intra-tumor heterogeneity of cancer cells hampers the design of effective therapies and yet it is poorly reproduced in experimental models. A recent report by Eirew at al. provides an in-depth analysis of genetic heterogeneity of breast tumor xenografts and shows that changes in clonal diversity might not be stochastic.


    Directory of Open Access Journals (Sweden)

    Elena Brînduse


    Full Text Available Four elite clonal accessions of Vitis vinifera L., Chasselas doré variety were identified in a very old plantation, of 110 years, located in Valea Cãlugãreascã, on the St. Nicolas Monastery vineyard. The vines, grafted on the SO4 (Selection Oppenheim 4 rootstock, were planted in 2007 in the germplasm collection belonging to the Research and Development Institute for Viticulture and Enology, Valea Cãlugãreascã. The evaluation of elite clonal accessions focused on the duration of their phenological cycles, grape fertility and productivity, resistance to diseases, quantity and quality of the grapes production. The elite clonal accessions have been distinguished from Chasselas doré through the grape production which is double at one of elite and higher for the other elites as a results of the average weight of the grapes. The potential of sugar accumulations in the must was approximately twice at the elite clonal accessions, with balanced total acidity and pH values. The elites will be further studied for confirming the genetic stability and to propose the most competitive for homologation.


    NARCIS (Netherlands)



    To gain insight into the clonal organization of lymphoid organs, we studied the distribution in situ of donor-derived cells in near-physiological chimeras. We introduced RT7b fetal liver cells into nonirradiated congenic RT7a neonatal rats. The chimerism 6-20 wk after injection ranged from 0.3 to 20

  14. Aging in a long-lived clonal tree.

    Directory of Open Access Journals (Sweden)

    Dilara Ally

    Full Text Available From bacteria to multicellular animals, most organisms exhibit declines in survivorship or reproductive performance with increasing age ("senescence". Evidence for senescence in clonal plants, however, is scant. During asexual growth, we expect that somatic mutations, which negatively impact sexual fitness, should accumulate and contribute to senescence, especially among long-lived clonal plants. We tested whether older clones of Populus tremuloides (trembling aspen from natural stands in British Columbia exhibited significantly reduced reproductive performance. Coupling molecular-based estimates of clone age with male fertility data, we observed a significant decline in the average number of viable pollen grains per catkin per ramet with increasing clone age in trembling aspen. We found that mutations reduced relative male fertility in clonal aspen populations by about 5.8 x 10(-5 to 1.6 x 10(-3 per year, leading to an 8% reduction in the number of viable pollen grains, on average, among the clones studied. The probability that an aspen lineage ultimately goes extinct rises as its male sexual fitness declines, suggesting that even long-lived clonal organisms are vulnerable to senescence.

  15. Clonal outbreak of Plasmodium falciparum infection in eastern Panama. (United States)

    Obaldia, Nicanor; Baro, Nicholas K; Calzada, Jose E; Santamaria, Ana M; Daniels, Rachel; Wong, Wesley; Chang, Hsiao-Han; Hamilton, Elizabeth J; Arevalo-Herrera, Myriam; Herrera, Socrates; Wirth, Dyann F; Hartl, Daniel L; Marti, Matthias; Volkman, Sarah K


    Identifying the source of resurgent parasites is paramount to a strategic, successful intervention for malaria elimination. Although the malaria incidence in Panama is low, a recent outbreak resulted in a 6-fold increase in reported cases. We hypothesized that parasites sampled from this epidemic might be related and exhibit a clonal population structure. We tested the genetic relatedness of parasites, using informative single-nucleotide polymorphisms and drug resistance loci. We found that parasites were clustered into 3 clonal subpopulations and were related to parasites from Colombia. Two clusters of Panamanian parasites shared identical drug resistance haplotypes, and all clusters shared a chloroquine-resistance genotype matching the pfcrt haplotype of Colombian origin. Our findings suggest these resurgent parasite populations are highly clonal and that the high clonality likely resulted from epidemic expansion of imported or vestigial cases. Malaria outbreak investigations that use genetic tools can illuminate potential sources of epidemic malaria and guide strategies to prevent further resurgence in areas where malaria has been eliminated.

  16. Unexplained infertility: association with inherited thrombophilia. (United States)

    Fatini, Cinzia; Conti, Lucia; Turillazzi, Valentina; Sticchi, Elena; Romagnuolo, Ilaria; Milanini, Maria Novella; Cozzi, Cinzia; Abbate, Rosanna; Noci, Ivo


    Unexplained infertility represents one of the most common diagnoses in fertility care. Attention is being paid to the association between inherited thrombophilia and infertility causes. In this study we investigated the prevalence of inherited thrombophilia according to infertility causes. We studied Prothrombin gene G20210A mutation, Factor V Leiden, deficiencies in protein S and C and antithrombin in 930 Caucasian infertile women referred to Fertility Center of the Department of Sciences for Woman and Child's Health, University of Florence, of whom 230 with unexplained, 195 female and 283 male infertility, and in 240 women who have conceived naturally without hormonal stimulation therapy. A significant relationship between inherited thrombophilia [OR 95%CI 1.97 (1.05-3.68), p = 0.03] and unexplained infertility was observed, whereas no association between thrombophilia and female and male infertility was found. Significantly higher prevalence of prothrombin gene mutation in unexplained infertile women in comparison to that observed in fertile women was observed (5.7% vs 2.1% p = 0.04); the prevalence of the other thrombophilia determinants was higher, even if not significantly, in the unexplained infertile group. This study demonstrates the relationship between inherited thrombophilia and unexplained infertility, thus suggesting the contribution of genetic components in modulating unexplained infertility, behind anovulation, male and tubal factor. Copyright © 2012 Elsevier Ltd. All rights reserved.

  17. 77 FR 14700 - Streamlining Inherited Regulations (United States)


    ... April 3, 2012. \\1\\ 76 FR 75825. The Bureau received a joint request from several industry and consumer... Consumer Law Center. For the reasons described in the joint request for an extension, the Bureau is...; ] BUREAU OF CONSUMER FINANCIAL PROTECTION 12 CFR Chapter X Streamlining Inherited Regulations...

  18. Phylogenetics Exercise Using Inherited Human Traits (United States)

    Tuimala, Jarno


    A bioinformatics laboratory exercise based on inherited human morphological traits is presented. It teaches how morphological characters can be used to study the evolutionary history of humans using parsimony. The exercise can easily be used in a pen-and-paper laboratory, but if computers are available, a more versatile analysis can be carried…

  19. Antisense Oligonucleotide Therapy for Inherited Retinal Dystrophies

    NARCIS (Netherlands)

    Gerard, X.; Garanto Iglesias, A.; Rozet, J.M.; Collin, R.W.J.


    Inherited retinal dystrophies (IRDs) are an extremely heterogeneous group of genetic diseases for which currently no effective treatment strategies exist. Over the last decade, significant progress has been made utilizing gene augmentation therapy for a few genetic subtypes of IRD, although several

  20. Soft inheritance: challenging the modern synthesis

    Directory of Open Access Journals (Sweden)

    Eva Jablonka


    Full Text Available This paper presents some of the recent challenges to the Modern Synthesis of evolutionary theory, which has dominated evolutionary thinking for the last sixty years. The focus of the paper is the challenge of soft inheritance - the idea that variations that arise during development can be inherited. There is ample evidence showing that phenotypic variations that are independent of variations in DNA sequence, and targeted DNA changes that are guided by epigenetic control systems, are important sources of hereditary variation, and hence can contribute to evolutionary changes. Furthermore, under certain conditions, the mechanisms underlying epigenetic inheritance can also lead to saltational changes that reorganize the epigenome. These discoveries are clearly incompatible with the tenets of the Modern Synthesis, which denied any significant role for Lamarckian and saltational processes. In view of the data that support soft inheritance, as well as other challenges to the Modern Synthesis, it is concluded that that synthesis no longer offers a satisfactory theoretical framework for evolutionary biology.

  1. Epigenetic inheritance of proteostasis and ageing (United States)

    Li, Cheryl; Casanueva, Olivia


    Abundant evidence shows that the genome is not as static as once thought and that gene expression can be reversibly modulated by the environment. In some cases, these changes can be transmitted to the next generation even if the environment has reverted. Such transgenerational epigenetic inheritance requires that information be stored in the germline in response to exogenous stressors. One of the most elusive questions in the field of epigenetic inheritance is the identity of such inherited factor(s). Answering this question would allow us to understand how the environment can shape human populations for multiple generations and may help to explain the rapid rise in obesity and neurodegenerative diseases in modern society. It will also provide clues on how we might be able to reprogramme the epigenome to prevent transmission of detrimental phenotypes and identify individuals who might be at increased risk of disease. In this article, we aim to review recent developments in this field, focusing on research conducted mostly in the nematode Caenorhabditis elegans and mice, that link environmental modulators with the transgenerational inheritance of phenotypes that affect protein-folding homoeostasis and ageing. PMID:27744335

  2. Difficulties in Learning Inheritance and Polymorphism (United States)

    Liberman, Neomi; Beeri, Catriel; Kolikant, Yifat Ben-David


    This article reports on difficulties related to the concepts of inheritance and polymorphism, expressed by a group of 22 in-service CS teachers with an experience with the procedural paradigm, as they coped with a course on OOP. Our findings are based on the analysis of tests, questionnaires that the teachers completed in the course, as well as on…

  3. Inherited platelet disorders and oral health. (United States)

    Valera, Marie-Cécile; Kemoun, Philippe; Cousty, Sarah; Sie, Pierre; Payrastre, Bernard


    Platelets play a key role in thrombosis and hemostasis. Accumulation of platelets at the site of vascular injury is the first step in the formation of hemostatic plugs, which play a pivotal role in preventing blood loss after injury. Platelet adhesion at sites of injury results in spreading, secretion, recruitment of additional platelets, and formation of platelet aggregates. Inherited platelet disorders are rare causes of bleeding syndromes, ranging from mild bruising to severe hemorrhage. The defects can reflect deficiency or dysfunction of platelet surface glycoproteins, granule contents, cytoskeletal proteins, platelet pro-coagulant function, and signaling pathways. For instance, Bernard-Soulier syndrome and Glanzmann thrombasthenia are attributed to deficiencies of glycoprotein Ib/IX/V and GPIIb/IIIa, respectively, and are rare but severe platelet disorders. Inherited defects that impair platelet secretion and/or signal transduction are among the most common forms of mild platelet disorders and include gray platelet syndrome, Hermansky-Pudlak syndrome, and Chediak-Higashi syndrome. When necessary, desmopressin, antifibrinolytic agents, and transfusion of platelets remain the most common treatment of inherited platelet disorders. Alternative therapies such as recombinant activated factor VII are also available for a limited number of situations. In this review, we will discuss the management of patients with inherited platelet disorders in various clinical situations related to dental cares, including surgical intervention. © 2012 John Wiley & Sons A/S.

  4. A Simple Analysis of an Inherited Trait (United States)

    Aagaard, Stanley; Keller, Elhannan


    Described is a classroom activity for analyzing an inherited human trait, the ability to tast phenylthiocarbamide (PTC). Formulas for analyzing gene frequency are given for classroom and neighborhood samples. Additional tables include statistics on the ability to taste PTC and other easily sampled human traits. (MA)

  5. Genetic testing for inheritable cardiac channelopathies. (United States)

    Szepesváry, Eszter; Kaski, Juan Pablo


    Cardiac channelopathies are linked to an increased risk of ventricular arrhythmia and sudden death. This article reviews the clinical characteristics and genetic basis of common cardiac ion-channel diseases, highlights some genotype-phenotype correlations, and summarizes genetic testing for inheritable cardiac channelopathies.

  6. In Ovo Delivery of CpG DNA Reduces Avian Infectious Laryngotracheitis Virus Induced Mortality and Morbidity

    Directory of Open Access Journals (Sweden)

    Simrika Thapa


    Full Text Available Endosomal toll-like receptor-21 and -9 sense CpG DNA activating production of pro-inflammatory mediators with antimicrobial effects. Here, we investigated the induction of antiviral response of in ovo delivered CpG DNA against infectious laryngotracheitis virus (ILTV infection. We found that in ovo delivered CpG DNA significantly reduces ILTV infection pre-hatch correlating with the expression of IL-1β and increase of macrophages in lungs. As assessed in vitro, CpG DNA stimulated avian macrophages could be a potential source of IL-1β and other pro-inflammatory mediators. Since we also found that in ovo CpG DNA delivery maintains increased macrophages in the lungs post-hatch, we infected the chickens on the day of hatch with ILTV. We found that in ovo delivered CpG DNA significantly reduces mortality and morbidity resulting from ILTV infection encountered post-hatch. Thus, CpG DNA can be a candidate innate immune stimulant worthy of further investigation for the control of ILTV infection in chickens.

  7. Phase I clinical trial of CpG oligonucleotide 7909 (PF-03512676) in patients with previously treated chronic lymphocytic leukemia. (United States)

    Zent, Clive S; Smith, Brian J; Ballas, Zuhair K; Wooldridge, James E; Link, Brian K; Call, Timothy G; Shanafelt, Tait D; Bowen, Deborah A; Kay, Neil E; Witzig, Thomas E; Weiner, George J


    CpG oligonucleotide 7909 (CpG 7909, PF-03512676), a synthetic 24mer single stranded agonist of TLR9 expressed by B cells and plasmacytoid dendritic cells, is immunomodulatory and can cause activation-induced death of chronic lymphocytic leukemia (CLL) cells. We report a phase I study of CpG 7909 in 41 patients with early relapsed CLL. A single intravenous dose of CpG 7909 was well tolerated with no clinical effects and no significant toxicity up to 1.05 mg/kg. Single dose subcutaneous CpG 7909 had a maximum tolerated dose (MTD) of 0.45 mg/kg with dose limiting toxicity of myalgia and constitutional effects. Multiple weekly subcutaneous doses at the MTD were well tolerated. CpG 7909 administration induced immunologic changes in CLL and non-malignant cells that were dose and route dependent. We conclude that multidose therapy with subcutaneous CpG 7909 (0.45 mg/kg) could be used in future phase II combination clinical trials for CLL.

  8. Specific siRNA Downregulated TLR9 and Altered Cytokine Expression Pattern in Macrophage after CpG DNA Stimulation

    Institute of Scientific and Technical Information of China (English)

    BinQiao; BaohuaLi; XiuliYang; HongyongZhang; YiweiChu; YingWang; SidongXiong


    Bacterial CpG DNA or synthetic oligonucleotides (ODNs) that contain unmethylated CpG motifs (CpG ODN) can directly activate antigen-presenting cells (APCs) to secrete various cytokines through the intraceilular receptor TL R9. Cytokine profiles elicited by the actions of stimulatory CpG DNA on TLR9 expressed APCs are crucial to the subsequent immune responses. To date, cytokine profiles in APCs upon CpG ODN stimulation in vitro are not fully investigated. In the present study, vector-based siRNA was used to downregulate TLR9 expression. Cytokine profiles were observed in murine macrophage cell line RAW264.7 transfected with TLR9-siRNA plasmid uponCpG ODN stimulation. We found that not all the cytokine expressions by the macrophage were decreased whileTLR9 was downregulated. IL-12, TNF-α, IFN-γ and IL-1β expressions were significantly decreased, but IL-6, IFN-β and IL-10 expressions were not affected. Interestingly, the level of IFN-α was even increased. This alteration of cytokines produced by TLR9-downregulated APCs upon CpG ODN stimulation might indicate that the role of CpG DNA is more complicated in the pathogenesis and prevention of diseases. Cellular & Molecular Immunology. 2005;2(2):130-135.

  9. Legal Inheritance in the Republic of Kosovo

    Directory of Open Access Journals (Sweden)

    Dr.Sc. Hamdi Podvorica


    Full Text Available Legal inheritance is one of the most important institutions of inheritance law which regulates the process of legal transition of property of the decedent to one or several heirs. The establish-ment of the legal framework has brought about new reforms to the Inheritance Law. This has enabled the enrichment and functio-ning of the law. A particularly important step was taken towards regulation of legal procedures regarding to how courts, other or-gans and other persons should act regarding inheritance issues. Concretization of the legal authorizations of bodies authorized to enforce the procedure of processing hereditary property has estab-lished the legal basis for realization of the iso jure principle, accor-ding to which, at the moment of death of the person, the heirs gain the right of inheritance and the hereditary property is never left without a titleholder. This is a great advantage that we have noted in undertaking this analysis of the norms in this work, because leaving hereditary property for a longer period of time without a titleholder would render the property vulnerable to des-truction, theft and extermination. The goal of this paper is to avoid focusing only on finding the positive sides of the normative regulation of the legal inheritance process, but also in finding practical deficiencies that are weighing down at the moment on this important process in Kosovo, and in proposing measures for overcoming them. The dark side of the legal inheritance process is linked to the inefficiency of courts and the still fragile legal system in Kosovo. By implementing empirical methods, we have come to the con-clusion that the low number of judges in proportion with the huge number of cases has become a key liability for practical implemen-tation of the principle of initiating the legal procedure ex officio. The failure in enforcing this principle and initiating the procedu-res for processing of hereditary property by courts, even though they

  10. Immune secondary response and clonal selection inspired optimizers

    Institute of Scientific and Technical Information of China (English)

    Maoguo Gong; Licheng Jiao; Lining Zhang; Haifeng Du


    The immune system's ability to adapt its B cells to new types of antigen is powered by processes known as clonal selection and affinity maturation. When the body is exposed to the same antigen, immune system usually calls for a more rapid and larger response to the antigen, where B cells have the function of negative adjustment. Based on the clonal selection theory and the dynamic process of immune response, two novel artificial immune system algorithms, secondary response clonal programming algorithm (SRCPA) and secondary response clonal multi-objective algorithm (SRCMOA), are presented for solving single and multi-objective optimization problems, respectively. Clonal selection operator (CSO) and secondary response operator (SRO) are the main operators of SRCPA and SRCMOA. Inspired by the cional selection theory, CSO reproduces individuals and selects their improved maturated progenies after the affinity mat-uration process. SRO copies certain antibodies to a secondary pool, whose members do not participate in CSO, but these antibodies could be activated by some external stimulations. The update of the secondary pool pays more attention to maintain the population diversity. On the one hand, decimal-string representation makes SRCPA more suitable for solving high-dimensional function optimiza-tion problems. Special mutation and recombination methods are adopted in SRCPA to simulate the somatic mutation and receptor edit-ing process. Compared with some existing evolutionary algorithms, such as OGA/Q, IEA, IMCPA, BGA and AEA, SRCPA is shown to be able to solve complex optimization problems, such as high-dimensional function optimizations, with better performance. On the other hand, SRCMOA combines the Pareto-strength based fitness assignment strategy, CSO and SRO to solve multi-objective optimization problems. The performance comparison between SRCMOA, NSGA-Ⅱ, SPEA, and PAES based on eight well-known test problems shows that SRCMOA has better performance in

  11. Potential for clonal animals in longevity and ageing studies. (United States)

    Nilsson Sköld, Helen; Obst, Matthias


    Ageing is defined as a decline in reproductive and/or somatic performance over time, and as such is experienced by most organisms. Evolutionary theories explain ageing as a consequence of reduced selection pressure against mutations and reduced allocation to somatic maintenance in post-reproductive individuals. In addition, the fecundity of younger age-groups makes a more significant contribution than infinite maintenance of the parental body to the production of subsequent generations. However, in clonal animals, as well as in plants that reproduce by agametic cloning, the adult body is itself a reproductive unit that increases its fitness as a function of genet size. Given the apparent longevity of many such clonal organisms, species undergoing agametic cloning are often assumed to be non-ageing and even potentially immortal. Here, we present a brief overview of ageing in organisms undergoing agametic cloning, focusing on animals and molecular investigation. We discuss molecular and evolutionary aspects of ageing or non-ageing with respect to selection in clonal species. Of particular relevance to the search for potential mechanistic processes behind longevity is the notion that clonal organisms are frequently smaller than their obligate sexual counterparts. In conclusion, we find that while clonal animals also commonly age, evolutionary arguments together with empirical evidence suggest that they are likely to be long-lived and stress resistant at the genet level. However, theoretical modeling continues to predict the possibility of immortality, if the contribution from sexual reproduction is low. Future in-depth study of long-lived clones should present an excellent opportunity to discover novel mechanisms for renewal and long-term somatic maintenance and health.

  12. Stem cell clonality -- theoretical concepts, experimental techniques, and clinical challenges. (United States)

    Glauche, Ingmar; Bystrykh, Leonid; Eaves, Connie; Roeder, Ingo


    Here we report highlights of discussions and results presented at an International Workshop on Concepts and Models of Stem Cell Organization held on July 16th and 17th, 2012 in Dresden, Germany. The goal of the workshop was to undertake a systematic survey of state-of-the-art methods and results of clonality studies of tissue regeneration and maintenance with a particular emphasis on the hematopoietic system. The meeting was the 6th in a series of similar conceptual workshops, termed StemCellMathLab,(2) all of which have had the general objective of using an interdisciplinary approach to discuss specific aspects of stem cell biology. The StemCellMathLab 2012, which was jointly organized by the Institute for Medical Informatics and Biometry, Medical Faculty Carl Gustav Carus, Dresden University of Technology and the Institute for Medical Informatics, Statistics and Epidemiology, Medical Faculty, University of Leipzig, brought together 32 scientists from 8 countries, with scientific backgrounds in medicine, cell biology, virology, physics, computer sciences, bioinformatics and mathematics. The workshop focused on the following questions: (1) How heterogeneous are stem cells and their progeny? and (2) What are the characteristic differences in the clonal dynamics between physiological and pathophysiological situations? In discussing these questions, particular emphasis was placed on (a) the methods for quantifying clones and their dynamics in experimental and clinical settings and (b) general concepts and models for their description. In this workshop summary we start with an introduction to the current state of clonality research and a proposal for clearly defined terminology. Major topics of discussion include clonal heterogeneity in unperturbed tissues, clonal dynamics due to physiological and pathophysiological pressures and conceptual and technical issues of clone quantification. We conclude that an interactive cross-disciplinary approach to research in this

  13. Deoxyribonucleic acid (DNA) methyltransferase contributes to p16 promoter CpG island methylation in lung adenocarcinoma with smoking. (United States)

    Sun, Rongju; Liu, Jiahong; Wang, Bo; Ma, Lingyun; Quan, Xiaojiao; Chu, Zhixiang; Li, Tanshi


    In this study, the relationship between CpG island methylation and smoking and DNA methyltransferase in the occurrence and development of lung adenocarcinoma was explored by detecting p16 promoter methylation status. Protein and mRNA levels of p16 were detected by immunohistochemistry and in situ hybridization assays. p16 gene promoter and exon 1 CpG island locus Hap II sites methylation status was analyzed with the methylation-specific PCR. Only 4 of 40 p16-positive cases were detected to methylate on CpG islands with 10% methylating rate whereas 18 of p16-negative cases were methylated up to 36.73% of methylating rate. The methylating rates of both p16-positive and p16-negative groups were significantly different. 17 of 50 cases with smoking from total 89 lung adenocarcinoma cases were detected to methylate on CpG islands while only 5 of the remaining 39 non-smokers to methylate. The difference of the methylating rates in both smokers and non-smokers was significant to suggest the closely association of CpG island methylation of p16 with smoking. Furthermore, p16 promoter CpG islands were detected to methylate in 15 of 35 cases with higher DNA methyltransferase activity whereas only 7 detected to methylate in the remaining 54 cases with lower DNA methyltransferase activity. p16 promoter CpG island methylation likely made p16 expressing silence thus contributed to the tumorigenesis of lung adenocarcinoma. Smoking is likely to promote p16 CpG island methylation or by its effect of the activity and metabolism of DNA methyltransferase 1 (DNMT) on CpG island methylation status.

  14. A Phase I Clinical Trial of CpG Oligonucleotide 7909 (PF-03512676) in Patients with Previously Treated Chronic Lymphocytic Leukemia


    Zent, Clive S.; Smith, Brian J.; Ballas, Zuhair K.; Wooldridge, James E.; Link, Brian K.; Call, Timothy G; Shanafelt, Tait D; Bowen, Deborah A.; Kay, Neil E.; Witzig, Thomas E.; Weiner, George J


    CpG oligonucleotide 7909 (CpG 7909, PF-03512676), a synthetic 24mer single stranded agonist of TLR9 expressed by B cells and plasmacytoid dendritic cells, is immunomodulatory and can cause activation-induced death of chronic lymphocytic leukemia (CLL) cells. We report a phase I study of CpG 7909 in 41 patients with early relapsed CLL. A single intravenous dose of CpG 7909 was well tolerated with no clinical effects and no significant toxicity up to 1.05 mg/kg. Single dose subcutaneous CpG 790...

  15. Clonal growth: invasion or stability? A comparative study of clonal architecture and diversity in native and introduced lineages of Phragmites australis (Poaceae). (United States)

    Douhovnikoff, Vladimir; Hazelton, Eric L G


    • The characteristics of clonal growth that are advantageous in invasive plants can also result in native plants' ability to resist invasion. In Maine, we compared the clonal architecture and diversity of an invasive lineage (introduced Phragmites) and a noninvasive lineage (native Phragmites) present in much of North America. This study is the first on stand-scale diversity using a sample size and systematic spatial-sampling scheme adequate for characterizing clonal structure in Phragmites. Our questions included: (1) Does the structure and extent of clonal growth suggest that the potential for clonal growth contributes to the invasiveness of the introduced lineage? (2) Is clonal growth common in the native lineage, acting as a possible source of ecological resistance and resilience?• Microsatellite markers were used to measure clonal sizes, architecture, and diversity within each lineage in stands within four marshes in Maine.• Clonal diversity measures indicated that clonal growth was significantly greater in stands of the native lineage than in the introduced. While lineage was a consistent predictor of clonal diversity relative ranking, the marsh location was a much stronger predictor of the absolute range of these values.• Our results indicate an important role for clonal growth in the space consolidation of native Phragmites and could explain why the introduced lineage, with stronger competitive traits, has not replaced the native where they co-occur. These results with regard to clone size, size distributions, singleton occurrence, and clonal architecture provide some evidence for stand development that follows a genotypic initial floristics model. © 2014 Botanical Society of America, Inc.

  16. 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


    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...

  17. Association of the CpG methylation pattern of the proximal insulin gene promoter with type 1 diabetes. (United States)

    Fradin, Delphine; Le Fur, Sophie; Mille, Clémence; Naoui, Nadia; Groves, Chris; Zelenika, Diana; McCarthy, Mark I; Lathrop, Mark; Bougnères, Pierre


    The insulin (INS) region is the second most important locus associated with Type 1 Diabetes (T1D). The study of the DNA methylation pattern of the 7 CpGs proximal to the TSS in the INS gene promoter revealed that T1D patients have a lower level of methylation of CpG -19, -135 and -234 (p = 2.10(-16)) and a higher methylation of CpG -180 than controls, while methylation was comparable for CpG -69, -102, -206. The magnitude of the hypomethylation relative to a control population was 8-15% of the corresponding levels in controls and was correlated in CpGs -19 and -135 (r = 0.77) and CpG -135 and -234 (r = 0.65). 70/485 (14%) of T1D patients had a simultaneous decrease in methylation of CpG -19, -135, -234 versus none in 317 controls. CpG methylation did not correlate with glycated hemoglobin or with T1D duration. The methylation of CpG -69, -102, -180, -206, but not CpG -19, -135, -234 was strongly influenced by the cis-genotype at rs689, a SNP known to show a strong association with T1D. We hypothesize that part of this genetic association could in fact be mediated at the statistical and functional level by the underlying changes in neighboring CpG methylation. Our observation of a CpG-specific, locus-specific methylation pattern, although it can provide an epigenetic biomarker of a multifactorial disease, does not indicate whether the reported epigenetic pattern preexists or follows the establishment of T1D. To explore the effect of chronic hyperglycemia on CpG methylation, we studied non obese patients with type 2 diabetes (T2D) who were found to have decreased CpG-19 methylation versus age-matched controls, similar to T1D (p = 2.10(-6)) but increased CpG-234 methylation (p = 5.10(-8)), the opposite of T1D. The causality and natural history of the different epigenetic changes associated with T1D or T2D remain to be determined.

  18. Association of the CpG methylation pattern of the proximal insulin gene promoter with type 1 diabetes.

    Directory of Open Access Journals (Sweden)

    Delphine Fradin

    Full Text Available The insulin (INS region is the second most important locus associated with Type 1 Diabetes (T1D. The study of the DNA methylation pattern of the 7 CpGs proximal to the TSS in the INS gene promoter revealed that T1D patients have a lower level of methylation of CpG -19, -135 and -234 (p = 2.10(-16 and a higher methylation of CpG -180 than controls, while methylation was comparable for CpG -69, -102, -206. The magnitude of the hypomethylation relative to a control population was 8-15% of the corresponding levels in controls and was correlated in CpGs -19 and -135 (r = 0.77 and CpG -135 and -234 (r = 0.65. 70/485 (14% of T1D patients had a simultaneous decrease in methylation of CpG -19, -135, -234 versus none in 317 controls. CpG methylation did not correlate with glycated hemoglobin or with T1D duration. The methylation of CpG -69, -102, -180, -206, but not CpG -19, -135, -234 was strongly influenced by the cis-genotype at rs689, a SNP known to show a strong association with T1D. We hypothesize that part of this genetic association could in fact be mediated at the statistical and functional level by the underlying changes in neighboring CpG methylation. Our observation of a CpG-specific, locus-specific methylation pattern, although it can provide an epigenetic biomarker of a multifactorial disease, does not indicate whether the reported epigenetic pattern preexists or follows the establishment of T1D. To explore the effect of chronic hyperglycemia on CpG methylation, we studied non obese patients with type 2 diabetes (T2D who were found to have decreased CpG-19 methylation versus age-matched controls, similar to T1D (p = 2.10(-6 but increased CpG-234 methylation (p = 5.10(-8, the opposite of T1D. The causality and natural history of the different epigenetic changes associated with T1D or T2D remain to be determined.

  19. A downstream CpG island controls transcript initiation and elongation and the methylation state of the imprinted Airn macro ncRNA promoter.

    Directory of Open Access Journals (Sweden)

    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.

  20. Comparative drug susceptibility study of five clonal strains of Trichomonas vaginalis in vitro

    Institute of Scientific and Technical Information of China (English)

    Hemantkumar Somabhai Chaudhari; Prati Pal Singh


    Objective: To produce comparative data on a group of Trichomonas vaginalis clonal strains with varied drug responses using identical methods and materials. Methods: Five clonal strains of Trichomonas vaginalis were isolated from reference strain using agar plate technique. The variability of growth kinetic and susceptibility of clonal strain to metronidazole, tinidazole, satranidazole and nitazoxanide were observed in 96 well microtitre plate. Results: Among these clonal strains there was a good correlation between rates of growth with the relative susceptibility of the strains to drugs in vitro. Regarding metronidazole, tinidazole and satranidazole susceptibility, different degrees of susceptibility were determined. However, no difference in nitazoxanide susceptibility was found between the clonal strain tested and a reference strain.Conclusions: This is the first description of biological variability in clonal stock of Trichomonas vaginalis. Different degrees of drug susceptibility were determined among clonal strains tested. Further studies will be necessary to ascertain the importance of this variability in clinical infection.

  1. Systematic review of pregnancy in women with inherited cardiomyopathies

    NARCIS (Netherlands)

    Krul, Sebastien P. J.; van der Smagt, Jasper J.; van den Berg, Maarten P.; Sollie, Krystyna M.; Pieper, Petronella G.; van Spaendonck-Zwarts, Karin Y.


    Pregnancy exposes women with inherited cardiomyopathies to increased risk for heart failure and arrhythmias. In this paper, we review the clinical course and management of pregnant women with the following inherited cardiomyopathies: hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmogeni

  2. Maternal inheritance and mitochondrial DNA variants in familial Parkinson's disease

    National Research Council Canada - National Science Library

    Simon, David K; Pankratz, Nathan; Kissell, Diane K; Pauciulo, Michael W; Halter, Cheryl A; Rudolph, Alice; Pfeiffer, Ronald F; Nichols, William C; Foroud, Tatiana


    .... We examined the possibility of a maternal inheritance bias as well as the association between mitochondrial haplogroups and maternal inheritance and disease risk in a case-control study of 168...

  3. Many Early Colon Cancers Linked to Inherited Genes (United States)

    ... Many Early Colon Cancers Linked to Inherited Genes One in 6 diagnosed ... inherited condition. It increases the rate of many cancers, including colon cancer, according to the U.S. National Library of ...

  4. Impact of SNPs on CpG Islands in the MYC and HRAS oncogenes and in a wide variety of tumor suppressor genes: A multi-cancer approach. (United States)

    Samy, Mohammad D; Yavorski, John M; Mauro, James A; Blanck, George


    Single nucleotide polymorphisms (SNPs) that occur within CpG Islands may lead to increased hypermethylation if a SNP allele has the potential to form a CpG dinucleotide, as well as potentially lead to hypomethylation if a SNP allele eliminates a CpG dinucleotide. We analyzed CpG-related SNP allele frequencies in whole genome sequences (WGS) across 5 TCGA cancer datasets, thereby exploiting a more recent appreciation for signaling pathway degeneracy in cancer. The cancer data sets were analyzed for SNPs in CpG islands associated with the oncogenes, HRAS and MYC, and in the CpG islands associated with the tumor suppressor genes, APC, DCC, and RB1. We determined that one SNP allele (rs3824120) in a CpG island associated with MYC which eliminated a CpG was more common in the cancer datasets than in the 100Genomes databases (p < 0.01). For HRAS, 2 SNP alleles (rs112690925, rs7939028) that created CpG's occurred significantly less frequently in the cancer data sets than in the general SNP databases (e.g., rs7939028, p < 0.0002, in comparison with AllSNPs(142)). Also, one SNP allele (rs4940177) that created a CpG in a CpG island associated with the DCC tumor suppressor gene, was more common in the cancer datasets (p < 0.0007). To understand a broader picture of the potential of SNP alleles to create CpG's in CpG islands of tumor suppressor genes, we developed a scripted algorithm to assess the SNP alleles associated with the CpG islands of 43 tumor suppressor genes. The following tumor suppressor genes have the possibility of significant, percent increases in their CpG counts, depending on which SNP allele(s) is present: VHL, BRCA1, BRCA2, CHEK2, PTEN and RB1.


    Institute of Scientific and Technical Information of China (English)


    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.

  6. [The many facets of inherited skin fragility]. (United States)

    Has, C; Kiritsi, D


    The inherited skin fragility encompasses a heterogeneous group of disorders, collectively designated as epidermolysis bullosa, characterized by recurrent mechanically induced blisters, erosions or wounds. The spectrum of clinical manifestations is broad, as well as the molecular background. Besides the skin, mucosal membranes and other organs can be affected. In real-world practice, patients with mild genetic skin fragility usually do not require medical care and often remain underdiagnosed. In contrast, the well-defined severe EB subtypes are recognized based on typical clinical features. The molecular diagnostics is usually performed in order to allow genetic counselling and prenatal diagnosis. Besides wound care and careful management of the disease complications, new experimental targeted therapies are being developed. New very rare forms of inherited skin fragility have been identified with modern sequencing methods.

  7. Management of inherited atherogenic dyslipidemias in children. (United States)

    Guardamagna, Ornella; Cagliero, Paola; Abello, Francesca


    In order to prevent cardiovascular disease, the treatment of inherited dyslipidemias in childhood represents an emerging topic capturing scientists' consideration. A body of findings emerged in the last decade for diagnosis and therapy, and results were recently summarized to introduce new guidelines by the American Academy of Pediatrics and National Institute for Health and Clinical Excellence. It is well known and generally shared the need to detect affected children precociously, when the family history address to genetic dyslipidemia and when familial premature cardiovascular disease occurs. A spectrum of disorders involving lipoproteins could be recognized by specific biochemical and genetic markers. A defined diagnosis represents the starting point to establish a correct treatment and follow-up program. This review represents a literature synthesis of the main cornerstones and criticisms concerning the screening program and management of atherogenic inherited dyslipidemias in children and adolescents.

  8. Mechanisms of Uniparental Mitochondrial DNA Inheritance in Cryptococcus neoformans


    Gyawali, Rachana; Lin, Xiaorong


    In contrast to the nuclear genome, the mitochondrial genome does not follow Mendelian laws of inheritance. The nuclear genome of meiotic progeny comes from the recombination of both parental genomes, whereas the meiotic progeny could inherit mitochondria from one, the other, or both parents. In fact, one fascinating phenomenon is that mitochondrial DNA in the majority of eukaryotes is inherited from only one particular parent. Typically, such unidirectional and uniparental inheritance of mito...

  9. Population thinking and natural selection in dual-inheritance theory


    Houkes, WN Wybo


    A deflationary perspective on theories of cultural evolution, in particular dual-inheritance theory, has recently been proposed by Lewens. On this ‘pop-culture’ analysis, dual-inheritance theorists apply population thinking to cultural phenomena, without claiming that cultural items evolve by natural selection. This paper argues against this pop-culture analysis of dual-inheritance theory. First, it focuses on recent dual-inheritance models of specific patterns of cultural change. These model...

  10. Normal epigenetic inheritance in mice conceived by in vitro fertilization and embryo transfer

    Institute of Scientific and Technical Information of China (English)

    Lei LI; Fang LE; Li-ya WANG; Xiang-rong XU; Hang-ying LOU; Ying-ming ZHENG; Jiang-zhong SHENG; He-feng HUANG; Fan JIN


    An association between assisted reproductive technology (ART) and neurobehavioral imprinting disorders has been reported in many studies,and it seems that ART may interfere with imprint reprogramming.However,it has never been explored whether epigenetic errors or imprinting disease susceptibility induced by ART can be inherited transgenerationally.Hence,the aim of this study was to determine the effect of in vitro fertilization and embryo transfer (IVF-ET) on transgenerational inheritance in an inbred mouse model.Mice derived from IVF-ET were outcrossed to wild-type C57BL/6J to obtain their female and male line F2 and F3 generations.Their behavior,morphology,histology,and DNA methylation status at several important differentially methylated regions (DMRs) were analyzed by Morris water maze,hematoxylin and eosin (H&E) staining,and bisulfite genomic sequencing.No significant differences in spatial learning or phenotypic abnormality were found in adults derived from IVF (F1) and female and male line F2 and F3 generations.A borderline trend of hypomethylation was found in H19 DMR CpG island 3 in the female line-derived F3 generation (0.40±0.118,P=0.086).Methylation status in H19/Igf2 DMR island 1,Igf2 DMR,KvDMR,and Snrpn DMR displayed normal patterns.Methylation percentage did not differ significantly from that of adults conceived naturally,and the expression of the genes they regulated was not disturbed.Transgenerational integrity,such as behavior,morphology,histology,and DNA methylation status,was maintained in these generations,which indicates that exposure of female germ cells to hormonal stimulation and gamete manipulation might not affect the individuals and their descendents.

  11. CoCanCPG. Coordination of cancer clinical practice in Europe. (United States)

    Fervers, Bèatrice; Remy-Stockinger, Magali; Mazeau-Woynar, Valèrie; Otter, Renèe; Liberati, Alessandro; Littlejohns, Peter; Qureshi, Safia; Vlayen, Joan; Characiejus, Dainius; Corbacho, Belèn; Garner, Sarah; Hamza-Mohamed, Farida; Hermosilla, Teresa; Kersten, Sonja; Kulig, Michael; Leshem, Benny; Levine, Nava; Ballini, Luciana; Middelton, Clifford; Mlika-Cabane, Najoua; Paquet, Louise; Podmaniczki, Erzsèbet; Ramaekers, Dirk; Robinson, Eliezer; Sanchez, Emilia; Philip, Thierry


    All European countries are facing common challenges for delivering appropriate, evidence-based care to patients with cancer. Despite tangible improvements in diagnosis and treatment, marked differences in cancer survival exist throughout Europe. The reliable translation of new research evidence into consistent patient-oriented strategies is a key endeavour to overcome inequalities in healthcare. Clinical-practice guidelines are important tools for improving quality of care by informing professionals and patients about the most appropriate clinical practice. Guideline programmes in different countries use similar strategies to achieve similar goals. This results in unnecessary duplication of effort and inefficient use of resources. While different initiatives at the international level have attempted to improve the quality of guidelines, less investment has been made to overcome existing fragmentation and duplication of effort in cancer guideline development and research. To provide added value to existing initiatives and foster equitable access to evidence-based cancer care in Europe, CoCanCPG will establish cooperation between cancer guideline programmes. CoCanCPG is an ERA-Net coordinated by the French National Cancer Institute with 17 partners from 11 countries. The CoCanCPG partners will achieve their goal through an ambitious, stepwise approach with a long-term perspective, involving: 1. implementing a common framework for sharing knowledge and skills; 2. developing shared activities for guideline development; 3. assembling a critical mass for pertinent research into guideline methods; 4. implementing an appropriate framework for cooperation. Successful development of joint activities involves learning how to adopt common quality standards and how to share responsibilities, while taking into account the cultural and organisational diversity of the participating organisations. Languages barriers and different organisational settings add a level of complexity to

  12. CpG islands influence chromatin structure via the CpG-binding protein Cfp1. (United States)

    Thomson, John P; Skene, Peter J; Selfridge, Jim; Clouaire, Thomas; Guy, Jacky; Webb, Shaun; Kerr, Alastair R W; Deaton, Aimée; Andrews, Rob; James, Keith D; Turner, Daniel J; Illingworth, Robert; Bird, Adrian


    CpG islands (CGIs) are prominent in the mammalian genome owing to their GC-rich base composition and high density of CpG dinucleotides. Most human gene promoters are embedded within CGIs that lack DNA methylation and coincide with sites of histone H3 lysine 4 trimethylation (H3K4me3), irrespective of transcriptional activity. In spite of these intriguing correlations, the functional significance of non-methylated CGI sequences with respect to chromatin structure and transcription is unknown. By performing a search for proteins that are common to all CGIs, here we show high enrichment for Cfp1, which selectively binds to non-methylated CpGs in vitro. Chromatin immunoprecipitation of a mono-allelically methylated CGI confirmed that Cfp1 specifically associates with non-methylated CpG sites in vivo. High throughput sequencing of Cfp1-bound chromatin identified a notable concordance with non-methylated CGIs and sites of H3K4me3 in the mouse brain. Levels of H3K4me3 at CGIs were markedly reduced in Cfp1-depleted cells, consistent with the finding that Cfp1 associates with the H3K4 methyltransferase Setd1 (refs 7, 8). To test whether non-methylated CpG-dense sequences are sufficient to establish domains of H3K4me3, we analysed artificial CpG clusters that were integrated into the mouse genome. Despite the absence of promoters, the insertions recruited Cfp1 and created new peaks of H3K4me3. The data indicate that a primary function of non-methylated CGIs is to genetically influence the local chromatin modification state by interaction with Cfp1 and perhaps other CpG-binding proteins.

  13. Leukotriene B4 potentiates CpG signaling for enhanced cytokine secretion by human leukocytes. (United States)

    Gaudreault, Eric; Gosselin, Jean


    TLRs are known to be important in innate host defense against a variety of microbial infections. In particular, TLR9 has been associated with immune defense against different foreign organisms by recognition of unmethylated DNA sequences. In this report, we provide evidence that leukotriene B(4) (LTB(4)) has the capacity to modulate TLR9 expression on human neutrophils. The effect of LTB(4) was found to be specific, because related leukotrienes such as LTC(4) and LTD(4) or neutrophil agonists IL-8 and C5a failed to modulate TLR9 expression in neutrophils. Using fluorochrome-tagged CpG DNA, we observed that LTB(4) treatment also increased TLR9 ligand binding in neutrophils. Moreover, LTB(4) stimulation potentiates CpG-mediated signaling via an endosome-independent mechanism in human neutrophils, leading to enhanced secretion of proinflammatory cytokines. The increase in cytokine secretion by LTB(4) following CpG stimulation of neutrophils was associated with the activation of TGF-beta-activated kinase (TAK-1) as well as p38 and c-Jun (JNK) kinases. In contrast, in PBMC LTB(4) leads to an increase in cytokine secretion following CpG stimulation but via a MyD88- and endosome-dependent mechanism. As observed in neutrophils, PBMC stimulation with LTB(4) in the presence of CpG also results in enhanced TAK-1, p38, and JNK phosphorylation/activation. These data provide new evidence underlying the immunomodulatory properties of LTB(4) leading to antimicrobial defense.

  14. Methylation Linear Discriminant Analysis (MLDA for identifying differentially methylated CpG islands

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    Vass J Keith


    Full Text Available Abstract Background Hypermethylation of promoter CpG islands is strongly correlated to transcriptional gene silencing and epigenetic maintenance of the silenced state. As well as its role in tumor development, CpG island methylation contributes to the acquisition of resistance to chemotherapy. Differential Methylation Hybridisation (DMH is one technique used for genome-wide DNA methylation analysis. The study of such microarray data sets should ideally account for the specific biological features of DNA methylation and the non-symmetrical distribution of the ratios of unmethylated and methylated sequences hybridised on the array. We have therefore developed a novel algorithm tailored to this type of data, Methylation Linear Discriminant Analysis (MLDA. Results MLDA was programmed in R (version 2.7.0 and the package is available at CRAN 1. This approach utilizes linear regression models of non-normalised hybridisation data to define methylation status. Log-transformed signal intensities of unmethylated controls on the microarray are used as a reference. The signal intensities of DNA samples digested with methylation sensitive restriction enzymes and mock digested are then transformed to the likelihood of a locus being methylated using this reference. We tested the ability of MLDA to identify loci differentially methylated as analysed by DMH between cisplatin sensitive and resistant ovarian cancer cell lines. MLDA identified 115 differentially methylated loci and 23 out of 26 of these loci have been independently validated by Methylation Specific PCR and/or bisulphite pyrosequencing. Conclusion MLDA has advantages for analyzing methylation data from CpG island microarrays, since there is a clear rational for the definition of methylation status, it uses DMH data without between-group normalisation and is less influenced by cross-hybridisation of loci. The MLDA algorithm successfully identified differentially methylated loci between two classes of

  15. Significance of CpG methylation for solar UV-induced mutagenesis and carcinogenesis in skin. (United States)

    Ikehata, Hironobu; Ono, Tetsuya


    Mutations detected in the p53 gene in human nonmelanoma skin cancers show a highly UV-specific mutation pattern, a dominance of C --> T base substitutions at dipyrimidine sites plus frequent CC --> TT tandem substitutions, indicating a major involvement of solar UV in the skin carcinogenesis. These mutations also have another important characteristic of frequent occurrences at CpG dinucleotide sites, some of which actually show prominent hotspots in the p53 gene. Although mammalian solar UV-induced mutation spectra were studied intensively in the aprt gene using rodent cultured cells and the UV-specific mutation pattern was confirmed, the second characteristic of the p53 mutations in human skin cancers had not been reproduced. However, studies with transgenic mouse systems developed thereafter for mutation research, which harbor methyl CpG-abundant transgenes as mutation markers, yielded complete reproductions of the situation of the human skin cancer mutations in terms of both the UV-specific pattern and the frequent occurrence at CpG sites. In this review, we evaluate the significance of the CpG methylation for solar UV mutagenesis in the mammalian genome, which would lead to skin carcinogenesis. We propose that the UV-specific mutations at methylated CpG sites, C --> T transitions at methyl CpG-associated dipyrimidine sites, are a solar UV-specific mutation signature, and have estimated the wavelength range effective for the solar-UV-specific mutation as 310-340 nm. We also recommend the use of methyl CpG-enriched sequences as mutational targets for studies on solar-UV genotoxicity for human, rather than conventional mammalian mutational marker genes such as the aprt and hprt genes.

  16. CZ: Multimethods and Multiple Inheritance Without Diamonds (United States)


    renaming (e.g., Eiffel [31]) or by lin- earizing the class hierarchy [46, 45]. However, there is still no satisfactory solution to the dia- mond...the latter is the desirable semantics; it is supported in languages such as Scala, Eiffel , and C++ (the last through virtual inheritance) [38, 31, 21...certain. Previous Solutions. Languages that directly attempt to solve the object initialization problem include Eiffel [31], C++ [21], Scala [38] and

  17. Problem of technological inheritance in machine engineering (United States)

    Blumenstein, Valery; Rakhimyanov, Kharis; Heifetz, Mikhail; Kleptzov, Alexander


    This article demonstrates the importance of the research study with regard to the technological inheritance of the properties, which characterize the surface layer, at different stages of a part's life cycle. It looks back at the major achievements and gives the findings relating to the technological inheritance of the parameters of the surface layer strength and quality as well as to how they affect the performance properties of machine parts. It demonstrates that high rates of machine engineering development, occurrence of new materials and more complicated machine operation environment require a shorter period for design-to-manufacture facility by reducing experiments and increasing design work. That, in its turn, generates the necessity in more complex but also more accurate models of metal behavior under stressing. It is especially critical for strengthening treatment. Among them are the models developed within the mechanics of technological inheritance. It is assumed that at the stages of a part's life cycle deformation accumulates on a continuous basis and the plasticity reserve of the metal, which the surface layer is made of, depletes. The research study of technological inheritance and the discovery of physical patterns of the evolution and degradation of the structures in a thin surface layer, which occur during machining and operational stressing of parts made from existing and unique including nanopatterned metals, is a crucial scientific challenge. This leads to the acquisition of new knowledge in the plasticity of state-of-the-art metals in the conditions of complex non monotonous stressing and to the development of efficient integrated and combined methods of technological impact.

  18. Polyethyleneimine-functionalized boron nitride nanospheres as efficient carriers for enhancing the immunostimulatory effect of CpG oligodeoxynucleotides

    Directory of Open Access Journals (Sweden)

    Zhang HJ


    Full Text Available Huijie Zhang,1 Shini Feng,1 Ting Yan,1 Chunyi Zhi,2 Xiao-Dong Gao,1 Nobutaka Hanagata3,41The Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi, People’s Republic of China; 2Department of Physics and Materials Science, City University of Hong Kong, Kowlong, Hong Kong SAR, People’s Republic of China; 3Biomaterials Unit, International Center for Materials Nanoarchitectonics, National Institute for Materials Science, Ibaraki, Japan; 4Nanotechnology Innovation Station, National Institute for Materials Science, Ibaraki, JapanAbstract: CpG oligodeoxynucleotides (ODNs stimulate innate and adaptive immune responses. Thus, these molecules are promising therapeutic agents and vaccine adjuvants against various diseases. In this study, we developed a novel CpG ODNs delivery system based on polyethyleneimine (PEI-functionalized boron nitride nanospheres (BNNS. PEI was coated on the surface of BNNS via electrostatic interactions. The prepared BNNS–PEI complexes had positive zeta potential and exhibited enhanced dispersity and stability in aqueous solution. In vitro cytotoxicity assays revealed that the BNNS–PEI complexes with concentrations up to 100 µg/mL exhibited no obvious cytotoxicity. Furthermore, the positively charged surface of the BNNS–PEI complexes greatly improved the loading capacity and cellular uptake efficiency of CpG ODNs. Class B CpG ODNs loaded on the BNNS–PEI complexes enhanced the production of interleukin-6 and tumor necrosis factor-α from peripheral blood mononuclear cells compared with CpG ODNs directly loaded on BNNS. Contrary to the free CpG ODNs or CpG ODNs directly loaded on BNNS, class B CpG ODNs loaded on the BNNS–PEI complexes induced interferon-α simultaneously. PEI coating may have changed the physical form of class B CpG ODNs on BNNS, which further affected their interaction with Toll-like receptor 9 and induced interferon

  19. Phenotype as Agent for Epigenetic Inheritance

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    John S. Torday


    Full Text Available The conventional understanding of phenotype is as a derivative of descent with modification through Darwinian random mutation and natural selection. Recent research has revealed Lamarckian inheritance as a major transgenerational mechanism for environmental action on genomes whose extent is determined, in significant part, by germ line cells during meiosis and subsequent stages of embryological development. In consequence, the role of phenotype can productively be reconsidered. The possibility that phenotype is directed towards the effective acquisition of epigenetic marks in consistent reciprocation with the environment during the life cycle of an organism is explored. It is proposed that phenotype is an active agent in niche construction for the active acquisition of epigenetic marks as a dominant evolutionary mechanism rather than a consequence of Darwinian selection towards reproductive success. The reproductive phase of the life cycle can then be appraised as a robust framework in which epigenetic inheritance is entrained to affect growth and development in continued reciprocal responsiveness to environmental stresses. Furthermore, as first principles of physiology determine the limits of epigenetic inheritance, a coherent justification can thereby be provided for the obligate return of all multicellular eukaryotes to the unicellular state.

  20. Paternal inheritance in mealybugs (Hemiptera: Coccoidea: Pseudococcidae). (United States)

    Kol-Maimon, Hofit; Mendel, Zvi; Franco, José Carlos; Ghanim, Murad


    Mealybugs have a haplodiploid reproduction system, with paternal genome elimination (PGE); the males are diploid soon after fertilization, but during embryogenesis, the male paternal set of chromosomes becomes heterochromatic (HC) and therefore inactive. Previous studies have suggested that paternal genes can be passed on from mealybug males to their sons, but not necessarily by any son, to the next generation. We employed crosses between two mealybug species--Planococcus ficus (Signoret) and Planococcus citri (Risso)--and between two populations of P. ficus, which differ in their mode of pheromone attraction, in order to demonstrate paternal inheritance from males to F2 through F1 male hybrids. Two traits were monitored through three generations: mode of male pheromone attraction (pherotype) and sequences of the internal transcribed spacer 2 (ITS2) gene segment (genotype). Our results demonstrate that paternal inheritance in mealybugs can occur from males to their F2 offspring, through F1 males (paternal line). F2 backcrossed hybrid males expressed paternal pherotypes and ITS2 genotypes although their mother originated through a maternal population. Further results revealed other, hitherto unknown, aspects of inheritance in mealybugs, such as that hybridization between the two species caused absence of paternal traits in F2 hybrid females produced by F1 hybrid females. Furthermore, hybridization between the two species raised the question of whether unattracted males have any role in the interactions between P. ficus and P. citri.

  1. Inheritance of Electronic Payment Accounts: Practice Issues

    Directory of Open Access Journals (Sweden)

    Kirillova EA


    Full Text Available This article describes the inheritance of electronic payment accounts (wallets, such as Yandex Money, WebMoney, and similar. In terms of safety and ease, electronic money calculation is the most promising calculation method in Internet. Payments with non-cash settlements are much more beneficial from all points of view. They greatly accelerate the payment process, simplify it, and help to reduce transaction costs. This is most clearly seen in the example, where the buyer and seller are located in a distance from each other in different countries. In development of the electronic money and online money transactions, a question occurs about the legal aspects and the rights of the heirs of the electronic payment accounts. This topic is relevant today, as almost every person every day faces in the electronic payments, but not everyone knows what they are and how they operate. The main objective of the study is to determine the legal status of the electronic payment accounts and the possibility of their inheritance by law. A lot of scientists devoted their works to the problems of studying the theoretical foundations of the electronic payment system, its place and role in the financial system, and its development. However, for the first time the legal matter of inheritance is considered from the practical aspect, wherein the novelty of the present study lays. The article concludes on the need to verify the owner of the electronic wallet for the rights of his heirs.

  2. Wide Dispersion and Diversity of Clonally Related Inhibitory Interneurons. (United States)

    Harwell, Corey C; Fuentealba, Luis C; Gonzalez-Cerrillo, Adrian; Parker, Phillip R L; Gertz, Caitlyn C; Mazzola, Emanuele; Garcia, Miguel Turrero; Alvarez-Buylla, Arturo; Cepko, Constance L; Kriegstein, Arnold R


    The mammalian neocortex is composed of two major neuronal cell types with distinct origins: excitatory pyramidal neurons and inhibitory interneurons, generated in dorsal and ventral progenitor zones of the embryonic telencephalon, respectively. Thus, inhibitory neurons migrate relatively long distances to reach their destination in the developing forebrain. The role of lineage in the organization and circuitry of interneurons is still not well understood. Utilizing a combination of genetics, retroviral fate mapping, and lineage-specific retroviral barcode labeling, we find that clonally related interneurons can be widely dispersed while unrelated interneurons can be closely clustered. These data suggest that migratory mechanisms related to the clustering of interneurons occur largely independent of their clonal origin.

  3. Clonal Selection Algorithm Based Iterative Learning Control with Random Disturbance

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    Yuanyuan Ju


    Full Text Available Clonal selection algorithm is improved and proposed as a method to solve optimization problems in iterative learning control. And a clonal selection algorithm based optimal iterative learning control algorithm with random disturbance is proposed. In the algorithm, at the same time, the size of the search space is decreased and the convergence speed of the algorithm is increased. In addition a model modifying device is used in the algorithm to cope with the uncertainty in the plant model. In addition a model is used in the algorithm cope with the uncertainty in the plant model. Simulations show that the convergence speed is satisfactory regardless of whether or not the plant model is precise nonlinear plants. The simulation test verify the controlled system with random disturbance can reached to stability by using improved iterative learning control law but not the traditional control law.

  4. Immune clonal selection optimization method with combining mutation strategies

    Institute of Scientific and Technical Information of China (English)


    In artificial immune optimization algorithm, the mutation of immune cells has been considered as the key operator that determines the algorithm performance. Traditional immune optimization algorithms have used a single mutation operator, typically a Gaussian. Using a variety of mutation operators that can be combined during evolution to generate different probability density function could hold the potential for producing better solutions with less computational effort. In view of this, a linear combination mutation operator of Gaussian and Cauchy mutation is presented in this paper, and a novel clonal selection optimization method based on clonal selection principle is proposed also. The simulation results show the combining mutation strategy can obtain the same performance as the best of pure strategies or even better in some cases.

  5. Complex Antigens Drive Permissive Clonal Selection in Germinal Centers. (United States)

    Kuraoka, Masayuki; Schmidt, Aaron G; Nojima, Takuya; Feng, Feng; Watanabe, Akiko; Kitamura, Daisuke; Harrison, Stephen C; Kepler, Thomas B; Kelsoe, Garnett


    Germinal center (GC) B cells evolve toward increased affinity by a Darwinian process that has been studied primarily in genetically restricted, hapten-specific responses. We explored the population dynamics of genetically diverse GC responses to two complex antigens-Bacillus anthracis protective antigen and influenza hemagglutinin-in which B cells competed both intra- and interclonally for distinct epitopes. Preferred VH rearrangements among antigen-binding, naive B cells were similarly abundant in early GCs but, unlike responses to haptens, clonal diversity increased in GC B cells as early "winners" were replaced by rarer, high-affinity clones. Despite affinity maturation, inter- and intraclonal avidities varied greatly, and half of GC B cells did not bind the immunogen but nonetheless exhibited biased VH use, V(D)J mutation, and clonal expansion comparable to antigen-binding cells. GC reactions to complex antigens permit a range of specificities and affinities, with potential advantages for broad protection.

  6. Clonal propagation of chemically uniform fennel plants through somatic embryoids. (United States)

    Miura, Y; Fukui, H; Tabata, M


    Somatic embryoids obtained from cell suspension cultures of fennel in Linsmaier-Skoog medium containing 2,4-D and kinetin readily developed into plantlets when plated on a hormone-free agar medium. These plants were transplanted to the field to be tested for the uniformity of the chemically as well as the morphologically important characteristics of fruits. The results of field trials conducted for two years have confirmed that the clonal plants derived from somatic embryoids are remarkably uniform in all the characteristics examined in comparison with the control plants propagated through seeds. It is suggested, therefore, that the quality control of fennel fruits used for spice or medicine could be achieved by means of clonal propagation through somatic embryoids.

  7. Gene silencing of Nox4 by CpG island methylation during hepatocarcinogenesis in rats (United States)

    López-Álvarez, Guadalupe S.; Wojdacz, Tomasz K.; García-Cuellar, Claudia M.; Monroy-Ramírez, Hugo C.; Rodríguez-Segura, Miguel A.; Pacheco-Rivera, Ruth A.; Valencia-Antúnez, Carlos A.; Cervantes-Anaya, Nancy; Soto-Reyes, Ernesto; Vásquez-Garzón, Verónica R.; Sánchez-Pérez, Yesennia; Villa-Treviño, Saúl


    ABSTRACT The association between the downregulation of genes and DNA methylation in their CpG islands has been extensively studied as a mechanism that favors carcinogenesis. The objective of this study was to analyze the methylation of a set of genes selected based on their microarray expression profiles during the process of hepatocarcinogenesis. Rats were euthanized at: 24 h, 7, 11, 16 and 30 days and 5, 9, 12 and 18 months post-treatment. We evaluated the methylation status in the CpG islands of four deregulated genes (Casp3, Cldn1, Pex11a and Nox4) using methylation-sensitive high-resolution melting technology for the samples obtained from different stages of hepatocarcinogenesis. We did not observe methylation in Casp3, Cldn1 or Pex11a. However, Nox4 exhibited altered methylation patterns, reaching a maximum of 10%, even during the early stages of hepatocarcinogenesis. We observed downregulation of mRNA and protein of Nox4 (97.5% and 40%, respectively) after the first carcinogenic stimulus relative to the untreated samples. Our results suggest that Nox4 downregulation is associated with DNA methylation of the CpG island in its promoter. We propose that methylation is a mechanism that can silence the expression of Nox4, which could contribute to the acquisition of neoplastic characteristics during hepatocarcinogenesis in rats. PMID:27895046

  8. 5'-Cytosine-phosphoguanine (CpG) methylation impacts the activity of natural and engineered meganucleases. (United States)

    Valton, Julien; Daboussi, Fayza; Leduc, Sophie; Molina, Rafael; Redondo, Pilar; Macmaster, Rachel; Montoya, Guillermo; Duchateau, Philippe


    In this study, we asked whether CpG methylation could influence the DNA binding affinity and activity of meganucleases used for genome engineering applications. A combination of biochemical and structural approaches enabled us to demonstrate that CpG methylation decreases I-CreI DNA binding affinity and inhibits its endonuclease activity in vitro. This inhibition depends on the position of the methylated cytosine within the DNA target and was almost total when it is located inside the central tetrabase. Crystal structures of I-CreI bound to methylated cognate target DNA suggested a molecular basis for such inhibition, although the precise mechanism still has to be specified. Finally, we demonstrated that the efficacy of engineered meganucleases can be diminished by CpG methylation of the targeted endogenous site, and we proposed a rational design of the meganuclease DNA binding domain to alleviate such an effect. We conclude that although activity and sequence specificity of engineered meganucleases are crucial parameters, target DNA epigenetic modifications need to be considered for successful gene editions.

  9. Gaits-transferable CPG controller for a snake-like robot

    Institute of Scientific and Technical Information of China (English)

    LU Zhen Li; MA ShuGen; LI Bin; WANG YueChao


    With slim and legless body, particular ball articulation, and rhythmic locomotion, a nature snake adapted itself to many terrains under the control of a neuron system. Based on analyzing the locomotion mechanism, the main functional features of the motor system in snakes are specified in detail. Furthermore, a bidirectional cyclic inhibitory (BCI) CPG model is applied for the first time to imitate the pattern gen- eration for the locomotion control of the snake-like robot, and its characteristics are discussed, particularly for the generation of three kinds of rhythmic locomotion. Moreover, we introduce the neuron network organized by the BCI-CPGs connected in line with unilateral excitation to switch automatically locomotion pattern of a snake-like robot under different commands from the higher level control neuron and present a necessary condition for the CPG neuron network to sustain a rhythmic output. The validity for the generation of different kinds of rhythmic lo- comotion modes by the CPG network are verified by the dynamic simulations and experiments. This research provided a new method to model the generation mechanism of the rhythmic pattern of the snake.

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

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    Robert Illingworth


    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.

  11. Gene silencing of Nox4 by CpG island methylation during hepatocarcinogenesis in rats

    Directory of Open Access Journals (Sweden)

    Guadalupe S. López-Álvarez


    Full Text Available The association between the downregulation of genes and DNA methylation in their CpG islands has been extensively studied as a mechanism that favors carcinogenesis. The objective of this study was to analyze the methylation of a set of genes selected based on their microarray expression profiles during the process of hepatocarcinogenesis. Rats were euthanized at: 24 h, 7, 11, 16 and 30 days and 5, 9, 12 and 18 months post-treatment. We evaluated the methylation status in the CpG islands of four deregulated genes (Casp3, Cldn1, Pex11a and Nox4 using methylation-sensitive high-resolution melting technology for the samples obtained from different stages of hepatocarcinogenesis. We did not observe methylation in Casp3, Cldn1 or Pex11a. However, Nox4 exhibited altered methylation patterns, reaching a maximum of 10%, even during the early stages of hepatocarcinogenesis. We observed downregulation of mRNA and protein of Nox4 (97.5% and 40%, respectively after the first carcinogenic stimulus relative to the untreated samples. Our results suggest that Nox4 downregulation is associated with DNA methylation of the CpG island in its promoter. We propose that methylation is a mechanism that can silence the expression of Nox4, which could contribute to the acquisition of neoplastic characteristics during hepatocarcinogenesis in rats.

  12. Dynamic Modelling of a CPG-Controlled Amphibious Biomimetic Swimming Robot

    Directory of Open Access Journals (Sweden)

    Rui Ding


    Full Text Available This paper focuses on the modelling and control problems of a self‐propelled, multimodal amphibious robot. Inspired by the undulatory body motions of fish and dolphins, the amphibious robot propels itself underwater by oscillations of several modular fish‐like propelling units coupled with a pair of pectoral fins capable of non‐continuous 360 degree rotation. In order to mimic fish‐like undulating propulsion, a control architecture based on Central Pattern Generator (CPG is applied to the amphibious robot for robust swimming gaits, including forward and backward swimming and turning, etc. With the simplification of the robot as a multi‐link serial mechanism, a Lagrangian function is employed to establish the hydrodynamic model for steady swimming. The CPG motion control law is then imported into the Lagrangian‐based dynamic model, where an associated system of kinematics and dynamics is formed to solve real‐time movements and, further, to guide the exploration of the CPG parameters and steady locomotion gaits. Finally, comparative results between the simulations and experiments are provided to show the effectiveness of the built control models.

  13. CpG DNA: A pathogenic factor in systemic lupus erythematosus?

    Energy Technology Data Exchange (ETDEWEB)

    Krieg, A.M. [Univ. of Iowa College of Medicine, Iowa City, IA (United States)


    Systemic lupus erythematosus (SLE) is a multifactorial disease of unknown etiology. Characteristic features of SLE include (1) polyclonal B cell activation, (2) overexpression of the immune stimulatory cytokine interleukin-6 (IL-6), (3) defective tolerance to self antigens, and (4) production of anti-DNA antibodies (Ab). Bacterial infection has been suspected as a triggering factor for lupus. Bacterial DNA differs from vertebrate DNA in the frequency and methylation of CpG dinucleotides. These CpG motifs in bacterial DNA induce a variety of immune effects, including (1) polyclonal activation of murine and human B cells, (2) IL-6 secretion, and (3) resistance to apoptosis, thereby potentially allowing the survival of autoreactive cells. These results suggest that microbial DNA could therefore be a pathogenic factor in SLE. SLE patients have elevated levels of circulating plasma DNA which is reportedly enriched in hypomethylated CpGs. Genomic DNA is also hypomethylated in SLE. The purpose of this review is to summarize the immune effects of CpG motifs and to present the evidence for their possible involvement in the pathogenesis of SLE. 77 refs.

  14. Dynamic Modelling of a CPG-Controlled Amphibious Biomimetic Swimming Robot

    Directory of Open Access Journals (Sweden)

    Rui Ding


    Full Text Available This paper focuses on the modelling and control problems of a self-propelled, multimodal amphibious robot. Inspired by the undulatory body motions of fish and dolphins, the amphibious robot propels itself underwater by oscillations of several modular fish-like propelling units coupled with a pair of pectoral fins capable of non-continuous 360 degree rotation. In order to mimic fish-like undulating propulsion, a control architecture based on Central Pattern Generator (CPG is applied to the amphibious robot for robust swimming gaits, including forward and backward swimming and turning, etc. With the simplification of the robot as a multi-link serial mechanism, a Lagrangian function is employed to establish the hydrodynamic model for steady swimming. The CPG motion control law is then imported into the Lagrangian-based dynamic model, where an associated system of kinematics and dynamics is formed to solve real-time movements and, further, to guide the exploration of the CPG parameters and steady locomotion gaits. Finally, comparative results between the simulations and experiments are provided to show the effectiveness of the built control models.

  15. Synthetic CpG islands reveal DNA sequence determinants of chromatin structure (United States)

    Wachter, Elisabeth; Quante, Timo; Merusi, Cara; Arczewska, Aleksandra; Stewart, Francis; Webb, Shaun; Bird, Adrian


    The mammalian genome is punctuated by CpG islands (CGIs), which differ sharply from the bulk genome by being rich in G + C and the dinucleotide CpG. CGIs often include transcription initiation sites and display ‘active’ histone marks, notably histone H3 lysine 4 methylation. In embryonic stem cells (ESCs) some CGIs adopt a ‘bivalent’ chromatin state bearing simultaneous ‘active’ and ‘inactive’ chromatin marks. To determine whether CGI chromatin is developmentally programmed at specific genes or is imposed by shared features of CGI DNA, we integrated artificial CGI-like DNA sequences into the ESC genome. We found that bivalency is the default chromatin structure for CpG-rich, G + C-rich DNA. A high CpG density alone is not sufficient for this effect, as A + T-rich sequence settings invariably provoke de novo DNA methylation leading to loss of CGI signature chromatin. We conclude that both CpG-richness and G + C-richness are required for induction of signature chromatin structures at CGIs. DOI: PMID:25259796

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

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    CAI eLI


    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.

  17. CpG Oligodeoxynucleotides Induce Differential Cytokine and Chemokine Gene Expression Profiles in Dapulian and Landrace Pigs. (United States)

    Hu, Jiaqing; Yang, Dandan; Wang, Hui; Li, Chuanhao; Zeng, Yongqing; Chen, Wei


    Oligodeoxynucleotides containing unmethylated CpG motifs (CpG ODN) mimic the immunostimulatory activity of microbial DNA by interacting with Toll-like receptor 9 (TLR9) to activate both the innate and adaptive immune responses in different species. However, few studies have been published to compare the effects of CpG ODN on different pig breeds. Therefore, in this study, whole blood gene expression profiles of DPL and Landrace pigs treated with CpG ODN were studied using RNA-seq technology. Five Hundred differentially expressed genes (DEGs) were identified between the two breeds. DPL pigs had significantly higher number of immune-relevant DEGs than the Landrace pigs after CpG ODN treatment. Pathway analysis showed that cytokine-cytokine receptor interaction and chemokine signaling pathway were the major enriched pathways of the immune-relevant DEGs. Further in vitro experiments showed that PBMCs of the DPL pigs had significantly higher levels of TLR9 mRNA than those of the Landrace pigs, both before and after CpG ODN stimulation. Cytokine and chemokine induction in the PBMCs of both breeds were also measured after CpG ODN stimulation. Our data showed that mRNA levels of cytokines (IFNα, IL8, IL12 p40) and chemokines (CXCL9, CXCL13) were significantly higher in the PBMCs of the DPL pigs than those of the Landrace pigs. Taken together, our data provide new information regarding the pig breed difference in response to CpG ODN stimulation and that higher levels of TLR9 mRNA in DPL pigs may be a major contributor for disease resistance.

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

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    Omkar Byadgi


    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.

  19. CpG Oligodeoxynucleotides Induce Differential Cytokine and Chemokine Gene Expression Profiles in Dapulian and Landrace Pigs

    Directory of Open Access Journals (Sweden)

    Jiaqing Hu


    Full Text Available Oligodeoxynucleotides containing unmethylated CpG motifs (CpG ODN mimic the immunostimulatory activity of microbial DNA by interacting with Toll-like receptor 9 (TLR9 to activate both the innate and adaptive immune responses in different species. However, few studies have been published to compare the effects of CpG ODN on different pig breeds. Therefore, in this study, whole blood gene expression profiles of DPL and Landrace pigs treated with CpG ODN were studied using RNA-seq technology. 500 differentially expressed genes (DEGs were identified between the two breeds. DPL pigs had significantly higher number of immune-relevant DEGs than the Landrace pigs after CpG ODN treatment. Pathway analysis showed that cytokine-cytokine receptor interaction and chemokine signaling pathway were the major enriched pathways of the immune-relevant DEGs. Further in vitro experiments showed that PBMCs of the DPL pigs had significantly higher levels of TLR9 mRNA than those of the Landrace pigs, both before and after CpG ODN stimulation. Cytokine and chemokine induction in the PBMCs of both breeds were also measured after CpG ODN stimulation. Our data showed that mRNA levels of cytokines (IFNα, IL8, IL12 p40 and chemokines (CXCL9, CXCL13 were significantly higher in the PBMCs of the DPL pigs than those of the Landrace pigs. Taken together, our data provide new information regarding the pig breed difference in response to CpG ODN stimulation and that higher levels of TLR9 mRNA in DPL pigs may be a major contributor for disease resistance.

  20. Streptococcus mutans Clonal Variation Revealed by Multilocus Sequence Typing▿


    Nakano, Kazuhiko; Lapirattanakul, Jinthana; Nomura, Ryota; Nemoto, Hirotoshi; Alaluusua, Satu; Grönroos, Lisa; Vaara, Martti; Hamada, Shigeyuki; Ooshima, Takashi; Nakagawa, Ichiro


    Streptococcus mutans is the major pathogen of dental caries, a biofilm-dependent infectious disease, and occasionally causes infective endocarditis. S. mutans strains have been classified into four serotypes (c, e, f, and k). However, little is known about the S. mutans population, including the clonal relationships among strains of S. mutans, in relation to the particular clones that cause systemic diseases. To address this issue, we have developed a multilocus sequence typing (MLST) scheme ...

  1. Clonality in seagrasses, emergent properties and seagrass landscapes


    Kendrick, Gary A.; Duarte, Carlos M.; Marbà, Núria


    Seagrasses are clonal monocots that dominate shallow subtidal coastal and estuarine environments worldwide. They are important for their relatively high productivity and their role in coastal sediment stabilization, as habitat and food for invertebrates, fishes, turtles, dugongs and manatees, and as a source for detrital food webs. Seagrasses grow through the iteration of a vegetative ramet, consisting of leaves capable of photosynthesizing attached to a shoot, a portion of rhizome and associ...

  2. A computational clonal analysis of the developing mouse limb bud.

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    Luciano Marcon

    Full Text Available A comprehensive spatio-temporal description of the tissue movements underlying organogenesis would be an extremely useful resource to developmental biology. Clonal analysis and fate mappings are popular experiments to study tissue movement during morphogenesis. Such experiments allow cell populations to be labeled at an early stage of development and to follow their spatial evolution over time. However, disentangling the cumulative effects of the multiple events responsible for the expansion of the labeled cell population is not always straightforward. To overcome this problem, we develop a novel computational method that combines accurate quantification of 2D limb bud morphologies and growth modeling to analyze mouse clonal data of early limb development. Firstly, we explore various tissue movements that match experimental limb bud shape changes. Secondly, by comparing computational clones with newly generated mouse clonal data we are able to choose and characterize the tissue movement map that better matches experimental data. Our computational analysis produces for the first time a two dimensional model of limb growth based on experimental data that can be used to better characterize limb tissue movement in space and time. The model shows that the distribution and shapes of clones can be described as a combination of anisotropic growth with isotropic cell mixing, without the need for lineage compartmentalization along the AP and PD axis. Lastly, we show that this comprehensive description can be used to reassess spatio-temporal gene regulations taking tissue movement into account and to investigate PD patterning hypothesis.

  3. Clonal analysis of the microbiota of severe early childhood caries. (United States)

    Kanasi, E; Dewhirst, F E; Chalmers, N I; Kent, R; Moore, A; Hughes, C V; Pradhan, N; Loo, C Y; Tanner, A C R


    Severe early childhood caries is a microbial infection that severely compromises the dentition of young children. The aim of this study was to characterize the microbiota of severe early childhood caries. Dental plaque samples from 2- to 6-year-old children were analyzed using 16S rRNA gene cloning and sequencing, and by specific PCR amplification for Streptococcus mutans and Bifidobacteriaceae species. Children with severe caries (n = 39) had more dental plaque and gingival inflammation than caries-free children (n = 41). Analysis of phylotypes from operational taxonomic unit analysis of 16S rRNA clonal metalibraries from severe caries and caries-free children indicated that while libraries differed significantly (p diversity than detected in this clonal analysis. Using the Human Oral Microbiome Database, 139 different taxa were identified. Within the limits of this study, caries-associated taxa included Granulicatella elegans (p diverse microbiota that differed between severe caries and caries-free children, but the association of S. mutans with caries was from specific PCR analysis, not from clonal analysis, of samples. Copyright © 2010 S. Karger AG, Basel.

  4. Identification of genomic features in environmentally induced epigenetic transgenerational inherited sperm epimutations.

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    Carlos Guerrero-Bosagna

    Full Text Available A variety of environmental toxicants have been shown to induce the epigenetic transgenerational inheritance of disease and phenotypic variation. The process involves exposure of a gestating female and the developing fetus to environmental factors that promote permanent alterations in the epigenetic programming of the germline. The molecular aspects of the phenomenon involve epigenetic modifications (epimutations in the germline (e.g. sperm that are transmitted to subsequent generations. The current study integrates previously described experimental epigenomic transgenerational data and web-based bioinformatic analyses to identify genomic features associated with these transgenerationally transmitted epimutations. A previously identified genomic feature associated with these epimutations is a low CpG density (<12/100bp. The current observations suggest the transgenerational differential DNA methylation regions (DMR in sperm contain unique consensus DNA sequence motifs, zinc finger motifs and G-quadruplex sequences. Interaction of molecular factors with these sequences could alter chromatin structure and accessibility of proteins with DNA methyltransferases to alter de novo DNA methylation patterns. G-quadruplex regions can promote the opening of the chromatin that may influence the action of DNA methyltransferases, or factors interacting with them, for the establishment of epigenetic marks. Zinc finger binding factors can also promote this chromatin remodeling and influence the expression of non-coding RNA. The current study identified genomic features associated with sperm epimutations that may explain in part how these sites become susceptible for transgenerational programming.

  5. Identification of genomic features in environmentally induced epigenetic transgenerational inherited sperm epimutations. (United States)

    Guerrero-Bosagna, Carlos; Weeks, Shelby; Skinner, Michael K


    A variety of environmental toxicants have been shown to induce the epigenetic transgenerational inheritance of disease and phenotypic variation. The process involves exposure of a gestating female and the developing fetus to environmental factors that promote permanent alterations in the epigenetic programming of the germline. The molecular aspects of the phenomenon involve epigenetic modifications (epimutations) in the germline (e.g. sperm) that are transmitted to subsequent generations. The current study integrates previously described experimental epigenomic transgenerational data and web-based bioinformatic analyses to identify genomic features associated with these transgenerationally transmitted epimutations. A previously identified genomic feature associated with these epimutations is a low CpG density (transgenerational differential DNA methylation regions (DMR) in sperm contain unique consensus DNA sequence motifs, zinc finger motifs and G-quadruplex sequences. Interaction of molecular factors with these sequences could alter chromatin structure and accessibility of proteins with DNA methyltransferases to alter de novo DNA methylation patterns. G-quadruplex regions can promote the opening of the chromatin that may influence the action of DNA methyltransferases, or factors interacting with them, for the establishment of epigenetic marks. Zinc finger binding factors can also promote this chromatin remodeling and influence the expression of non-coding RNA. The current study identified genomic features associated with sperm epimutations that may explain in part how these sites become susceptible for transgenerational programming.

  6. Interleukin-4 Induces CpG Site-Specific Demethylation of the Pendrin Promoter in Primary Human Bronchial Epithelial Cells

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    Giada Scantamburlo


    Full Text Available Pendrin is upregulated in bronchial epithelial cells following IL-4 stimulation via binding of STAT6 to an N4 GAS motif. Basal CpG methylation of the pendrin promoter is cell-specific. We studied if a correlation exists between IL-4 sensitivity and the CpG methylation status of the pendrin promoter in human bronchial epithelial cell models. Methods: Real-time PCR and pyrosequencing were used to respectively quantify pendrin mRNA levels and methylation of pendrin promoter, with and without IL-4 stimulation, in healthy and diseased primary HBE cells, as well as NCI-H292 cells. Results: Increases in pendrin mRNA after IL-4 stimulation was more robust in NCI-H292 cells than in primary cells. The amount of gDNA methylated varied greatly between the cell types. In particular, CpG site 90 located near the N4 GAS motif was highly methylated in the primary cells. An additional CpG site (90bis, created by a SNP, was found only in the primary cells. IL-4 stimulation resulted in dramatic demethylation of CpG sites 90 and 90bis in the primary cells. Conclusions: IL-4 induces demethylation of specific CpG sites within the pendrin promoter. These epigenetic alterations are cell type specific, and may in part dictate pendrin mRNA transcription.

  7. 双足机器人CPG控制研究%Research on Biped Robot Control Method Based on CPG

    Institute of Scientific and Technical Information of China (English)

    蒙伟斌; 沈润杰; 何斌; 萧蕴诗


    根据动物运动机制,提出了基于中枢模式发生器(central pattern generator,CPG)的双足机器人运动控制方法;采用Kimura神经元振荡器模型设计了双足机器人的CPG控制网络架构,分别用于控制双足机器人的髋关节、膝关节和踝关节.通过Matlab仿真和实体实验,验证了所设计的机器人CPG网络架构及双足机器人CPG控制方法的可行性和有效性.%Based on animal movement mechanism, the article proposed a bionic control method based on central pattern generator (CPG) to control the biped robot. In this paper, by using Kimura neural oscillator, a CPG control network is designed and the angles of the hips,knees and ankles were controlled by the output of CPG network. Both simulation in Matlab and experiments on real biped robot validate the feasibility and the efficiency of the CPG control network and CPG control method on biped robot.

  8. Therapeutic administration of a synthetic CpG oligodeoxynucleotide triggers formation of anti-CpG antibodies. (United States)

    Karbach, Julia; Neumann, Antje; Wahle, Claudia; Brand, Kathrin; Gnjatic, Sacha; Jäger, Elke


    The synthetic oligodeoxynucleotide CpG 7909, which contains unmethylated cytosine/guanine (CpG) motifs, has potent immunostimulatory effects when coadministered with NY-ESO-1 peptides or recombinant NY-ESO-1 protein, resulting in an enhanced cellular and humoral immune response against the vaccine antigen. In this study, we report the development of anti-CpG-ODN antibodies in 21 of 37 patients who received CpG 7909 either alone or as a vaccine adjuvant. Specific anti-CpG immunoglobulin G (IgG) antibody titers ranged from 1:400 to 1:100,000. The anti-CpG antibodies cross-reacted with other synthetic CpG-ODNs but not with the DNA of mixed bacterial vaccine and were shown to be phosphorothioate backbone specific. Vaccine-related severe side effects observed in some patients were most likely not related to the development of anti-CpG antibodies. In addition, anti-CpG antibodies did not have negative effects on the vaccine immune response. These results show that anti-CpG antibodies develop in humans against short unmethylated CpG dinucleotide sequences after administration of CpG 7909. Our data therefore substantiate the potency of CpG 7909 to directly stimulate human B-cells and suggest that anti-CpG antibody monitoring should be a part of ongoing and planned clinical trials with CpG-ODNs.

  9. Adjuvanted rush immunotherapy using CpG oligodeoxynucleotides in experimental feline allergic asthma. (United States)

    Reinero, Carol R; Cohn, Leah A; Delgado, Cherlene; Spinka, Christine M; Schooley, Elizabeth K; DeClue, Amy E


    Allergic asthma is driven by relative overexpression of Th2 cell-derived cytokines in response to aeroallergens. In independent studies, both allergen-specific rush immunotherapy (RIT) and CpG oligodeoxynucleotides (ODN) showed promise in blunting eosinophilic inflammation in a model of feline allergic asthma. We hypothesized that RIT using allergen and CpG ODN would work synergistically to dampen the asthmatic phenotype in experimentally asthmatic cats. Twelve cats with asthma induced using Bermuda grass allergen (BGA) were studied. Of these, six were administered adjuvanted BGA RIT using CpG ODN #2142; six were administered placebo (saline) RIT and later crossed over to adjuvanted RIT. Over 2 days, subcutaneous CpG ODN (0.5ng/kg) with BGA (increasing doses every 2h from 20 to 200microg) was administered. Adverse events were recorded and compared with historical controls. Percentage of eosinophils in bronchoalveolar lavage fluid (BALF), % peripheral CD4+CD25+ T regulatory cells (Tregs), lymphocyte proliferation in response to ConA, and cytokine concentrations in BALF were measured over 2 months. Group mean BALF % eosinophils for the adjuvanted RIT cats were significantly lower at week 1 and month 1 (p=0.03 for both), and marginally significantly lower at month 2 (p=0.09) compared with placebo RIT cats. By the end of the study, 8/12 treated cats had BALF % eosinophils within the reference range for healthy cats. Adjuvanted RIT, but not placebo RIT, cats had significant decreases in the ConA stimulation index over time (p=0.05). BALF IL-4 concentrations were significantly higher at week 1 in adjuvanted RIT cats compared with baseline and month 2, and also with placebo RIT cats at week 1. No significant differences were detected between treatments or over time for IL-10 or IFN-gamma concentrations in BALF or for %Tregs cells in peripheral blood. Adjuvanted RIT using CpG ODN in experimental feline asthma dampens eosinophilic airway inflammation. Adverse effects

  10. Evaluation of infection course in mice induced by L. major in presence of positively charged liposomes containing CpG ODN

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    Hesamoddin Hoseinjani


    Full Text Available Abstract An inoculation of virulent Leishmania major is known as leishmanization (LZ which is proven to be the most effective control measure against Cutaneous Leishmaniasis (CL. However, using LZ is restricted due to various side effects such as uncontrolled lesion development. In the present research, the efficacy of cationic nanoliposomes containing CpG oligodeoxynucleotides (CpG ODN as an improved adjuvant delivery system was studied to diminish the lesion development and infection course of L. major after inoculation into the mice. BALB/c mice were inoculated subcutaneously (SC with L. major plus empty DSPC, DSPC (CpG ODN, DSPC (Non CpG ODN, empty DMPC, DMPC (CpG ODN, DMPC (Non CpG ODN or HEPES buffer. The results showed that group of mice received DMPC (CpG ODN nanoliposomes developed a significantly smaller lesion and showed minimum number of L. major in the spleen and draining lymph nodes. In addition, using DMPC (CpG ODN liposomes resulted in a Th1 type of immune response with a preponderance of IgG2a isotype which is concurrent with the production of DMPC (CpG induced IFN-γ in the spleen of the mice. Taken together, the results suggested that immune modulation using DMPC (CpG ODN nanoliposomes might be a practical approach to improve the safety of LZ

  11. Correlating Dimensions of Inheritance Hierarchy with Complexity & Reuse

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    Nasib S. Gill


    Full Text Available Inheritance is the vital feature of any object oriented software which provides reuse of exiting classes for designing new classes. Higher reuse provides higher productivity and greater quality.Inheritance hierarchy is one of the very important artifacts targeted for measurement of reuse and reusability. Reuse through inheritance hierarchy can be measured from two dimensions- Depth and Breadth. Higher depth and breadth may increase complexity of software which makes the software difficult to understand and maintain. This paper aimed to correlate the depth and breadth of inheritance hierarchy with reuse and complexity of inheritance hierarchy using design oriented metrics.

  12. Mitochondrial inheritance is mediated by microtubules in mammalian cell division. (United States)

    Lawrence, Elizabeth; Mandato, Craig


    The mitochondrial network fragments and becomes uniformly dispersed within the cytoplasm when mammalian cells enter mitosis. Such morphology and distribution of mitochondria was previously thought to facilitate the stochastic inheritance of mitochondria by daughter cells. In contrast, we recently reported that mitochondria in dividing mammalian cells are inherited by an ordered mechanism of inheritance mediated by microtubules. We showed that mitochondria are progressively enriched at the cell equator and depleted at the poles throughout division. Furthermore, the mitochondrial distribution during division is dependent on microtubules, indicating an ordered inheritance strategy. The microtubule-mediated positioning of mitochondria in dividing mammalian cells may have functional consequences for cell division and/or mitochondrial inheritance.

  13. 双足跳跃机器人的适应性 CPG 运动控制%Adaptive Motion Control of a Biped Jumping Robot Based on CPG

    Institute of Scientific and Technical Information of China (English)

    王婷婷; 富生; 郭伟; 李满天; 孙立宁


    为解决双足跳跃机器人在突发状况下的适应性控制问题,依据生物中枢模式发生器(CPG)运动控制原理,建立了可变结构的 CPG 运动控制机制;模拟生物神经网络的自重构特性,在运动控制机制中添加了时间延迟响应环节,用于突发状况的判断与调节。在机器人肢体突发故障或运动受到限制时,此机制可通过对自身状态的感知自发地调整神经网络结构,以继续维持稳定的运动。最后,在仿真平台上验证了此控制机制在正常行走与肢体自由度突然受到限制2种情况下的控制效果。%For solving the adapt control problem of biped hopping robot in unexpected situations,we build a CPG control mechanism which is able to change its control structure according to robot motion status simulating the CPG control mechanism in animals.Imi-tating the self reconfigurable feature of animal control mechanism,a time delayed response link is added to this control mechanism,for judging and adjusting the robot motion under unexpected situations.When the limbs of robot suddenly fails or the motion of robot limb is restricted,this control mechanism can sponta-neously adjust the structure of neural network accord-ing to perception of the robot motion status,and main-tain stable hopping motion.Finally,this control mecha-nism is studied on a simulation platform under two situations:normal hopping and hopping when one robotlimb suddenly fails.

  14. Transgenerational inheritance: Models and mechanisms of non-DNA sequence-based inheritance. (United States)

    Miska, Eric A; Ferguson-Smith, Anne C


    Heritability has traditionally been thought to be a characteristic feature of the genetic material of an organism-notably, its DNA. However, it is now clear that inheritance not based on DNA sequence exists in multiple organisms, with examples found in microbes, plants, and invertebrate and vertebrate animals. In mammals, the molecular mechanisms have been challenging to elucidate, in part due to difficulties in designing robust models and approaches. Here we review some of the evidence, concepts, and potential mechanisms of non-DNA sequence-based transgenerational inheritance. We highlight model systems and discuss whether phenotypes are replicated or reconstructed over successive generations, as well as whether mechanisms operate at transcriptional and/or posttranscriptional levels. Finally, we explore the short- and long-term implications of non-DNA sequence-based inheritance. Understanding the effects of non-DNA sequence-based mechanisms is key to a full appreciation of heritability in health and disease.

  15. Chitosan-coated boron nitride nanospheres enhance delivery of CpG oligodeoxynucleotides and induction of cytokines

    Directory of Open Access Journals (Sweden)

    Zhang H


    Full Text Available Huijie Zhang,1,2 Song Chen,3 Chunyi Zhi,4 Tomohiko Yamazaki,1,2 Nobutaka Hanagata1,2,5 1Graduate School of Life Science, Hokkaido University, Sapporo, Japan; 2Biomaterials Unit, International Center for Materials Nanoarchitectonics, National Institute for Materials Science, Ibaraki, Japan; 3Japanese Society for the Promotion of Science, Tokyo, Japan; 4Department of Physics and Materials Science, City University of Hong Kong, Hong Kong, People’s Republic of China; 5Nanotechnology Innovation Station, Ibaraki, Japan Background: Cytosine-phosphate-guanine (CpG oligodeoxynucleotides activate Toll-like receptor 9, leading to induction of proinflammatory cytokines, which play an important role in induction and maintenance of innate and adaptive immune responses. Previously, we have used boron nitride nanospheres (BNNS as a carrier for delivery of unmodified CpG oligodeoxynucleotides to activate Toll-like receptor 9. However, because CpG oligodeoxynucleotides and BNNS are both negatively charged, electrostatic repulsion between them is likely to reduce the loading of CpG oligodeoxynucleotides onto BNNS. Therefore, the efficiency of uptake of CpG oligodeoxynucleotides is also limited and does not result in induction of a robust cytokine response. To ameliorate these problems, we developed a CpG oligodeoxynucleotide delivery system using chitosan-coated BNNS as a carrier. Methods: To facilitate attachment of CpG oligodeoxynucleotides onto the BNNS and improve their loading capacity, we prepared positively charged BNNS by coating them with chitosan preparations of three different molecular weights and used them as carriers for delivery of CpG oligodeoxynucleotides. Results: The zeta potentials of the BNNS-CS complexes were positive, and chitosan coating improved their dispersity and stability in aqueous solution compared with BNNS. The positive charge of the BNNS-CS complexes greatly improved the loading capacity and cellular uptake efficiency of CpG

  16. Inheritance and innovation of the Art

    Institute of Scientific and Technical Information of China (English)



    Art is a very important and popular cultural form,whose complex rich contents are related daily life. As a spiritual products,the art has taken great proportion in society,which has unlimited development trend. When we study the development of the arts,it is necessary to show the style inheritance and the innovation in its previous cultural basis. We should continue to learn from the life and continue to find new areas,new creative themes of creativity,new inspiration in the works and new forms of expression, so that we can promote the art of true innovation and prosperity.

  17. Extending the SSCLI to Support Dynamic Inheritance (United States)

    Redondo, Jose Manuel; Ortin, Francisco; Perez-Schofield, J. Baltasar Garcia

    This paper presents a step forward on a research trend focused on increasing runtime adaptability of commercial JIT-based virtual machines, describing how to include dynamic inheritance into this kind of platforms. A considerable amount of research aimed at improving runtime performance of virtual machines has converted them into the ideal support for developing different types of software products. Current virtual machines do not only provide benefits such as application interoperability, distribution and code portability, but they also offer a competitive runtime performance.

  18. Molecular Mechanisms of Inherited Demyelinating Neuropathies (United States)



    The past 15 years have witnessed the identification of more than 25 genes responsible for inherited neuropathies in humans, many associated with primary alterations of the myelin sheath. A remarkable body of work in patients, as well as animal and cellular models, has defined the clinical and molecular genetics of these illnesses and shed light on how mutations in associated genes produce the heterogeneity of dysmyelinating and demyelinating phenotypes. Here, we review selected recent developments from work on the molecular mechanisms of these disorders and their implications for treatment strategies. PMID:18803325

  19. Non-cell-autonomous driving of tumour growth supports sub-clonal heterogeneity. (United States)

    Marusyk, Andriy; Tabassum, Doris P; Altrock, Philipp M; Almendro, Vanessa; Michor, Franziska; Polyak, Kornelia


    Cancers arise through a process of somatic evolution that can result in substantial sub-clonal heterogeneity within tumours. The mechanisms responsible for the coexistence of distinct sub-clones and the biological consequences of this coexistence remain poorly understood. Here we used a mouse xenograft model to investigate the impact of sub-clonal heterogeneity on tumour phenotypes and the competitive expansion of individual clones. We found that tumour growth can be driven by a minor cell subpopulation, which enhances the proliferation of all cells within a tumour by overcoming environmental constraints and yet can be outcompeted by faster proliferating competitors, resulting in tumour collapse. We developed a mathematical modelling framework to identify the rules underlying the generation of intra-tumour clonal heterogeneity. We found that non-cell-autonomous driving of tumour growth, together with clonal interference, stabilizes sub-clonal heterogeneity, thereby enabling inter-clonal interactions that can lead to new phenotypic traits.

  20. Discovery of MLL1 binding units, their localization to CpG Islands, and their potential function in mitotic chromatin. (United States)

    Bina, Minou; Wyss, Phillip; Novorolsky, Elise; Zulkelfi, Noorfatin; Xue, Jing; Price, Randi; Fay, Matthew; Gutmann, Zach; Fogler, Brian; Wang, Daidong


    Mixed Lineage Leukemia 1 (MLL1) is a mammalian ortholog of the Drosophila Trithorax. In Drosophila, Trithorax complexes transmit the memory of active genes to daughter cells through interactions with Trithorax Response Elements (TREs). However, despite their functional importance, nothing is known about sequence features that may act as TREs in mammalian genomic DNA. By analyzing results of reported DNA binding assays, we identified several CpG rich motifs as potential MLL1 binding units (defined as morphemes). We find that these morphemes are dispersed within a relatively large collection of human promoter sequences and appear densely packed near transcription start sites of protein-coding genes. Genome wide analyses localized frequent morpheme occurrences to CpG islands. In the human HOX loci, the morphemes are spread across CpG islands and in some cases tail into the surrounding shores and shelves of the islands. By analyzing results of chromatin immunoprecipitation assays, we found a connection between morpheme occurrences, CpG islands, and chromatin segments reported to be associated with MLL1. Furthermore, we found a correspondence of reported MLL1-driven "bookmarked" regions in chromatin to frequent occurrences of MLL1 morphemes in CpG islands. Our results implicate the MLL1 morphemes in sequence-features that define the mammalian TREs and provide a novel function for CpG islands. Apparently, our findings offer the first evidence for existence of potential TREs in mammalian genomic DNA and the first evidence for a connection between CpG islands and gene-bookmarking by MLL1 to transmit the memory of highly active genes during mitosis. Our results further suggest a role for overlapping morphemes in producing closely packed and multiple MLL1 binding events in genomic DNA so that MLL1 molecules could interact and reside simultaneously on extended potential transcriptional maintenance elements in human chromosomes to transmit the memory of highly active genes

  1. The Role of Liposomal CpG ODN on the Course of L. major Infection in BALB/C Mice

    Directory of Open Access Journals (Sweden)

    H Hejazi


    Full Text Available "nBackground: Historically, leishmanization is the most effective protective measure against Cutaneous Leishmaniasis (CL, CL lesion induced by leishmanization sometimes takes a long time to heal. Ma­nipulation of leishmanization inoculums needed to induce a mild and acceptable CL lesion. The aim of this study was to explore if liposomal form of CpG ODN (Cytosin phosphate Guanin Oligodeoxynu­cleotides mixed with Leishmania major   would induce a milder lesion size in Balb/c mice."nMethods: This study was performed in Biotechnology Research Center, Mashhad, and Center for Re­search and Training in Skin Diseases and Leprosy, Tehran, Iran during 2008-2009.  mice were subcutaneously (SC inoculated with L. major mixed with liposomal form of CpG ODN, or L. major plus free CpG ODN, or L. major mixed with empty liposomes or L. major in PBS. The lesion onset and the size of lesion were recorded; the death rate was also monitored. "nResult: Footpad thickness was significantly (P<0.01 smaller, death rate was also significantly (P<0.05 lower in the mice received L. major mixed with liposomal CpG ODN or free CpG ODN than control groups received L. major in PBS or L. major plus liposomes, also mice which received L. ma­jor mixed with CpG ODN in soluble form showed a significantly (P < 0.001 smaller lesion size than control groups."nConclusion: CpG ODN seems to be an appropriate immunopotentiator mixed with Leishmania stabi­late in leishmanization.

  2. Neuromuscular imaging in inherited muscle diseases

    Energy Technology Data Exchange (ETDEWEB)

    Wattjes, Mike P. [VU University Medical Center, Department of Radiology, De Boelelaan 1117, HV, Amsterdam (Netherlands); Kley, Rudolf A. [Klinken Bergmannsheil, Ruhr-University, Department of Neurology, Neuromuscular Centre Ruhrgebiet, Bochum (Germany); Fischer, Dirk [University Hospital of Basel, Department of Neurology, Basel (Switzerland); University Children' s Hospital Basel, Department of Neuropaediatrics, Basel (Switzerland)


    Driven by increasing numbers of newly identified genetic defects and new insights into the field of inherited muscle diseases, neuromuscular imaging in general and magnetic resonance imaging (MRI) in particular are increasingly being used to characterise the severity and pattern of muscle involvement. Although muscle biopsy is still the gold standard for the establishment of the definitive diagnosis, muscular imaging is an important diagnostic tool for the detection and quantification of dystrophic changes during the clinical workup of patients with hereditary muscle diseases. MRI is frequently used to describe muscle involvement patterns, which aids in narrowing of the differential diagnosis and distinguishing between dystrophic and non-dystrophic diseases. Recent work has demonstrated the usefulness of muscle imaging for the detection of specific congenital myopathies, mainly for the identification of the underlying genetic defect in core and centronuclear myopathies. Muscle imaging demonstrates characteristic patterns, which can be helpful for the differentiation of individual limb girdle muscular dystrophies. The aim of this review is to give a comprehensive overview of current methods and applications as well as future perspectives in the field of neuromuscular imaging in inherited muscle diseases. We also provide diagnostic algorithms that might guide us through the differential diagnosis in hereditary myopathies. (orig.)

  3. Atypical inheritance: new horizons for neurology. (United States)

    Wilson, G N


    Rediscovery of Mendel's laws produced an enthusiastic new discipline at the turn of this century. The eugenics movement had many disciples in the United States, and it should be noted that the term "final solution" was first used by the National Association of Charities and Corrections in the 1920s. American advocates of eugenics accomplished mass sterilization of retarded individuals and the prohibition of Jewish immigration from Germany during World War II. It is interesting that the close of this century has produced a similar revolution in genetics. These newer genetic mechanisms expose the major fallacy of eugenics: traits may be genetic without showing obvious familial transmission. Sanctions against reproduction or immigration thus will have little effect on the gene pool. The clinical implications of atypical inheritance are enormous. Almost every medical disorder must be reinvestigated for evidence of subtle chromosome changes, for worsening in progressive generations, and for influence of parental origin. The classical Mendelian model taught that extreme and rare phenotypes shed light on more frequent ones, hence the definition of genes responsible for hypercholesterolemia, for Alzheimer disease, and for amyotrophic lateral sclerosis. Atypical inheritance mechanisms further enhance this approach, bringing all of neurology under the light of genetic technology. The lure for the practitioner, then, is not the hyperbole of molecular biology; it is the need for a seasoned hand so emphasized by Huntington's disease and the duty to protect the next century from disasters of the current one.

  4. Digenic Inheritance in Cystinuria Mouse Model.

    Directory of Open Access Journals (Sweden)

    Meritxell Espino

    Full Text Available Cystinuria is an aminoaciduria caused by mutations in the genes that encode the two subunits of the amino acid transport system b0,+, responsible for the renal reabsorption of cystine and dibasic amino acids. The clinical symptoms of cystinuria relate to nephrolithiasis, due to the precipitation of cystine in urine. Mutations in SLC3A1, which codes for the heavy subunit rBAT, cause cystinuria type A, whereas mutations in SLC7A9, which encodes the light subunit b0,+AT, cause cystinuria type B. By crossing Slc3a1-/- with Slc7a9-/- mice we generated a type AB cystinuria mouse model to test digenic inheritance of cystinuria. The 9 genotypes obtained have been analyzed at early (2- and 5-months and late stage (8-months of the disease. Monitoring the lithiasic phenotype by X-ray, urine amino acid content analysis and protein expression studies have shown that double heterozygous mice (Slc7a9+/-Slc3a1+/- present lower expression of system b0,+ and higher hyperexcretion of cystine than single heterozygotes (Slc7a9+/-Slc3a1+/+ and Slc7a9+/+Slc3a1+/- and give rise to lithiasis in 4% of the mice, demonstrating that cystinuria has a digenic inheritance in this mouse model. Moreover in this study it has been demonstrated a genotype/phenotype correlation in type AB cystinuria mouse model providing new insights for further molecular and genetic studies of cystinuria patients.

  5. Inherited cardiomyopathies caused by troponin mutations

    Institute of Scientific and Technical Information of China (English)

    Qun-Wei Lu; Xiao-Yan Wu; Sachio Morimoto


    Genetic investigations of cardiomyopathy in the recent two decades have revealed a large number of mutations in the genes encoding sarcomeric proteins as a cause of inherited hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), or restrictive cardiomyopathy (RCM). Most functional analyses of the effects of mutations on cardiac muscle contraction have revealed significant changes in the Ca2+-regulatory mechanism, in which cardiac troponin (cTn) plays important structural and functional roles as a key regulatory protein. Over a hundred mutations have been identified in all three subunits of cTn, i.e., cardiac troponins T, I, and C. Recent studies on cTn mutations have provided plenty of evidence that HCM- and RCM-linked mutations increase cardiac myofilament Ca2+ sensitivity, while DCM-linked mutations decrease it. This review focuses on the functional consequences of mutations found in cTn in terms of cardiac myofilament Ca2+ sensitivity, ATPase activity, force generation, and cardiac troponin I phosphorylation, to understand potential molecular and cellular pathogenic mechanisms of the three types of inherited cardiomyopathy.

  6. Diagnostic significance of TCR gene clonal rearrangement analysis in early mycosis fungoides

    Institute of Scientific and Technical Information of China (English)

    Chen Xu; Chuan Wan; Lin Wang; Han-Jun Yang; Yuan Tang; Wei-Ping Liu


    Mycosis fungoides (MF), the most common type of cutaneous T-cell lymphoma, has various unspecific clinical and histological characteristics. Its eariy diagnosis is challenging. The application of T-cell receptor (TCR) gene clonal rearrangement to the diagnosis of MF has been widely studied. In this study, we used polymerase chain reaction (PCR) to investigate the diagnostic significance of detecting TCR-γ and -β gene clonal rearrangement in the eady diagnosis of mycosis fungoides. PCR for TCR-γ and TCR-β gene rearrangement was performed on 19 patients with suspected early MF, 6 with typical MF, and 6 with chronic dermatitis. Of the 19 patients with suspected eady MF, 13 had TCR-~ gene clonal rearrangement, whereas none had TCR-β gene clonal rearrangement. All patients with typical MF had TCR gene clonal rearrangement, in which 4 showed TCR-γ clonal rearrangement, 1 showed TCR-β gene clonal rearrangements, and 1 showed both. No patients with chronic dermatitis had TCR gene clonal rearrangement. These results indicate that TCR gene clonal rearrangement analysis is a useful tool in diagnosing early MF. TCR-γ gene is recommended to the routine analysis, whereas TCR-β gene has potential in combination toward intractable cases.

  7. Invasive clonal plant species have a greater root-foraging plasticity than non-invasive ones. (United States)

    Keser, Lidewij H; Dawson, Wayne; Song, Yao-Bin; Yu, Fei-Hai; Fischer, Markus; Dong, Ming; van Kleunen, Mark


    Clonality is frequently positively correlated with plant invasiveness, but which aspects of clonality make some clonal species more invasive than others is not known. Due to their spreading growth form, clonal plants are likely to experience spatial heterogeneity in nutrient availability. Plasticity in allocation of biomass to clonal growth organs and roots may allow these plants to forage for high-nutrient patches. We investigated whether this foraging response is stronger in species that have become invasive than in species that have not. We used six confamilial pairs of native European clonal plant species differing in invasion success in the USA. We grew all species in large pots under homogeneous or heterogeneous nutrient conditions in a greenhouse, and compared their nutrient-foraging response and performance. Neither invasive nor non-invasive species showed significant foraging responses to heterogeneity in clonal growth organ biomass or in aboveground biomass of clonal offspring. Invasive species had, however, a greater positive foraging response in terms of root and belowground biomass than non-invasive species. Invasive species also produced more total biomass. Our results suggest that the ability for strong root foraging is among the characteristics promoting invasiveness in clonal plants.

  8. Spatial niche facilitates clonal reproduction in seed plants under temporal disturbance.

    Directory of Open Access Journals (Sweden)

    Shin Fukui

    Full Text Available The evolutionary origins and advantages of clonal reproduction relative to sexual reproduction have been discussed for several taxonomic groups. In particular, organisms with a sessile lifestyle are often exposed to spatial and temporal environmental fluctuations. Thus, clonal propagation may be advantageous in such fluctuating environments, for sessile species that can reproduce both sexually and clonally. Here we introduce the concept of niche to a lattice space that changes spatially and temporally, by incorporating the compatibility between the characteristics of a sessile clonal plant with its habitat into a spatially explicit individual-based model. We evaluate the impact of spatially and temporally heterogeneous environments on the evolution of reproductive strategies: the optimal balance between seed and clonal reproduction of a clonal plant. The spatial niche case with local habitats led to avoidance of specialization in reproductive strategy, whereas stable environments or intensive environmental change tended to result in specialization in either clonal or seed reproduction under neutral conditions. Furthermore, an increase in spatial niches made clonal reproduction advantageous, as a consequence of competition among several genets under disturbed conditions, because a ramet reached a favorable habitat through a rare long-distance dispersal event via seed production. Thus, the existence of spatial niches could explain the advantages of clonal propagation.

  9. Spatial niche facilitates clonal reproduction in seed plants under temporal disturbance. (United States)

    Fukui, Shin; Araki, Kiwako S


    The evolutionary origins and advantages of clonal reproduction relative to sexual reproduction have been discussed for several taxonomic groups. In particular, organisms with a sessile lifestyle are often exposed to spatial and temporal environmental fluctuations. Thus, clonal propagation may be advantageous in such fluctuating environments, for sessile species that can reproduce both sexually and clonally. Here we introduce the concept of niche to a lattice space that changes spatially and temporally, by incorporating the compatibility between the characteristics of a sessile clonal plant with its habitat into a spatially explicit individual-based model. We evaluate the impact of spatially and temporally heterogeneous environments on the evolution of reproductive strategies: the optimal balance between seed and clonal reproduction of a clonal plant. The spatial niche case with local habitats led to avoidance of specialization in reproductive strategy, whereas stable environments or intensive environmental change tended to result in specialization in either clonal or seed reproduction under neutral conditions. Furthermore, an increase in spatial niches made clonal reproduction advantageous, as a consequence of competition among several genets under disturbed conditions, because a ramet reached a favorable habitat through a rare long-distance dispersal event via seed production. Thus, the existence of spatial niches could explain the advantages of clonal propagation.

  10. Clonal architectures and driver mutations in metastatic melanomas.

    Directory of Open Access Journals (Sweden)

    Li Ding

    Full Text Available To reveal the clonal architecture of melanoma and associated driver mutations, whole genome sequencing (WGS and targeted extension sequencing were used to characterize 124 melanoma cases. Significantly mutated gene analysis using 13 WGS cases and 15 additional paired extension cases identified known melanoma genes such as BRAF, NRAS, and CDKN2A, as well as a novel gene EPHA3, previously implicated in other cancer types. Extension studies using tumors from another 96 patients discovered a large number of truncation mutations in tumor suppressors (TP53 and RB1, protein phosphatases (e.g., PTEN, PTPRB, PTPRD, and PTPRT, as well as chromatin remodeling genes (e.g., ASXL3, MLL2, and ARID2. Deep sequencing of mutations revealed subclones in the majority of metastatic tumors from 13 WGS cases. Validated mutations from 12 out of 13 WGS patients exhibited a predominant UV signature characterized by a high frequency of C->T transitions occurring at the 3' base of dipyrimidine sequences while one patient (MEL9 with a hypermutator phenotype lacked this signature. Strikingly, a subclonal mutation signature analysis revealed that the founding clone in MEL9 exhibited UV signature but the secondary clone did not, suggesting different mutational mechanisms for two clonal populations from the same tumor. Further analysis of four metastases from different geographic locations in 2 melanoma cases revealed phylogenetic relationships and highlighted the genetic alterations responsible for differential drug resistance among metastatic tumors. Our study suggests that clonal evaluation is crucial for understanding tumor etiology and drug resistance in melanoma.


    Institute of Scientific and Technical Information of China (English)

    BU Zhao-jun; YANG Yun-fei; H(a)kan RYDIN; LANG Hui-qing


    Age structure of a plant population carries important information on population dynamics. The traditional age classification of individuals by development phases could not explain the generation relationship neither between individuals nor between modules, and it could not accurately predict the future of population or the tendency of peatland evolution. In a peatland of the Xiao Hinggan Mountains, China, at the middle of the growth season,the age structures of 3 modules, ramets, active buds and rhizomes of a Carex middendo(fii clonal population were investigated, with the method of classifying age classes of ramets and active buds by counting generation quantity of tiller nodes, and classifying age classes of rhizomes by their real survival time. The quantity of vegetative ramets was dominant. Tiller nodes oframets can propagate vegetatively for a maximum of 3 generations. The population of ramets consisted of 3 age classes of ramets at the middle of the growth season, and showed a stable age structure. In the two sampling events, there was no significant difference between quantities and age structure of the population.The maximum age of an excavated rhizome was 12 years old. Rhizomes were classified in 8 age classes, and age classes 4-6 contributed most to the total biomass. There was no significant difference in total length and total biomass per unit area, or in biomass per unit length in rhizomes between the two samplings. Four age classes of active buds were recognized, and their number increased from July to August. The Carex middendorffii clonal population achieved regeneration by budding from the tiller nodes of ramets. The age structures of the 3 modules suggested that the Carex middendorffii clonal population could persist in the early development phase of the oligotrophic peatland in the Xiao Hinggan Mountains, but it could not be dominant. It also faces the risk to disappear from the community as the peatland develops further.

  12. How past and present influence the foraging of clonal plants? (United States)

    Louâpre, Philipe; Bittebière, Anne-Kristel; Clément, Bernard; Pierre, Jean-Sébastien; Mony, Cendrine


    Clonal plants spreading horizontally and forming a network structure of ramets exhibit complex growth patterns to maximize resource uptake from the environment. They respond to spatial heterogeneity by changing their internode length or branching frequency. Ramets definitively root in the soil but stay interconnected for a varying period of time thus allowing an exchange of spatial and temporal information. We quantified the foraging response of clonal plants depending on the local soil quality sampled by the rooting ramet (i.e. the present information) and the resource variability sampled by the older ramets (i.e. the past information). We demonstrated that two related species, Potentilla reptans and P. anserina, responded similarly to the local quality of their environment by decreasing their internode length in response to nutrient-rich soil. Only P. reptans responded to resource variability by decreasing its internode length. In both species, the experience acquired by older ramets influenced the plastic response of new rooted ramets: the internode length between ramets depended not only on the soil quality locally sampled but also on the soil quality previously sampled by older ramets. We quantified the effect of the information perceived at different time and space on the foraging behavior of clonal plants by showing a non-linear response of the ramet rooting in the soil of a given quality. These data suggest that the decision to grow a stolon or to root a ramet at a given distance from the older ramet results from the integration of the past and present information about the richness and the variability of the environment.

  13. Phenotype-Specific CpG Island Methylation Events in a Murine Model of Prostate Cancer (United States)

    Camoriano, Marta; Morey Kinney, Shannon R.; Moser, Michael T.; Foster, Barbara A.; Mohler, James L.; Trump, Donald L.; Karpf, Adam R.; Smiraglia, Dominic J.


    Aberrant DNA methylation plays a significant role in nearly all human cancers and may contribute to disease progression to advanced phenotypes. Study of advanced prostate cancer phenotypes in the human disease is hampered by limited availability of tissues. We therefore took advantage of the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) model to study whether three different phenotypes of TRAMP tumors (PRIM, late-stage primary tumors; AIP, androgen-independent primary tumors; and MET, metastases) displayed specific patterns of CpG island hypermethylation using Restriction Landmark Genomic Scanning. Each tumor phenotype displayed numerous hypermethylation events, with the most homogeneous methylation pattern in AIP and the most heterogeneous pattern in MET. Several loci displayed a phenotype-specific methylation pattern; the most striking pattern being loci methylated at high frequency in PRIM and AIP but rarely in MET. Examination of the mRNA expression of three genes, BC058385, Goosecoid, and Neurexin 2, which exhibited nonpromoter methylation, revealed increased expression associated with downstream methylation. Only methylated samples showed mRNA expression, in which tumor phenotype was a key factor determining the level of expression. The CpG island in the human orthologue of BC058385 was methylated in human AIP but not in primary androgen-stimulated prostate cancer or benign prostate. The clinical data show a proof-of-principle that the TRAMP model can be used to identify targets of aberrant CpG island methylation relevant to human disease. In conclusion, phenotype-specific hypermethylation events were associated with the overexpression of different genes and may provide new markers of prostate tumorigenesis. PMID:18519676

  14. Fluoroquinolone Resistance among Clonal Complex 1 Group B Streptococcus Strains

    Directory of Open Access Journals (Sweden)

    Alefiya Neemuchwala


    Full Text Available Fluoroquinolone resistance in group B Streptococcus is increasingly being reported worldwide. Here, we correlated fluoroquinolone resistance with mutations in gyrA, gyrB, parC, and parE genes, identified by mining whole-genome sequencing (WGS data of 190 clonal complex 1 group B Streptococcus strains recovered from patients with invasive diseases in North America. We report a high prevalence of fluoroquinolone resistance (12% among GBS strains in our collection. Our approach is the first step towards accurate prediction of fluoroquinolone resistance from WGS data in this opportunistic pathogen.

  15. Clonal origins of ETV6-RUNX1+ acute lymphoblastic leukemia

    DEFF Research Database (Denmark)

    Alpar, D.; Wren, D.; Ermini, Luca;


    Studies on twins with concordant acute lymphoblastic leukemia (ALL) have revealed that ETV6-RUNX1 gene fusion is a common, prenatal genetic event with other driver aberrations occurring subclonally and probably postnatally. The fetal cell type that is transformed by ETV6-RUNX1 is not identified...... by such studies or by the analysis of early B-cell lineage phenotype of derived progeny. Ongoing, clonal immunoglobulin (IG) and cross-lineage T-cell receptor (TCR) gene rearrangements are features of B-cell precursor leukemia and commence at the pro-B-cell stage of normal B-cell lineage development. We reasoned...

  16. Rapid and strong human CD8+ T cell responses to vaccination with peptide, IFA, and CpG oligodeoxynucleotide 7909. (United States)

    Speiser, Daniel E; Liénard, Danielle; Rufer, Nathalie; Rubio-Godoy, Verena; Rimoldi, Donata; Lejeune, Ferdy; Krieg, Arthur M; Cerottini, Jean-Charles; Romero, Pedro


    The induction of potent CD8+ T cell responses by vaccines to fight microbes or tumors remains a major challenge, as many candidates for human vaccines have proved to be poorly immunogenic. Deoxycytidyl-deoxyguanosin oligodeoxynucleotides (CpG ODNs) trigger Toll-like receptor 9, resulting in dendritic cell maturation that can enhance immunogenicity of peptide-based vaccines in mice. We tested whether a synthetic ODN, CpG 7909, could improve human tumor antigen-specific CD8+ T cell responses. Eight HLA-A2+ melanoma patients received 4 monthly vaccinations of low-dose CpG 7909 mixed with melanoma antigen A (Melan-A; identical to MART-1) analog peptide and incomplete Freund's adjuvant. All patients exhibited rapid and strong antigen-specific T cell responses: the frequency of Melan-A-specific T cells reached over 3% of circulating CD8+ T cells. This was one order of magnitude higher than the frequency seen in 8 control patients treated similarly but without CpG and 1-3 orders of magnitude higher than that seen in previous studies with synthetic vaccines. The enhanced T cell populations consisted primarily of effector memory cells, which in part secreted IFN- and expressed granzyme B and perforin ex vivo. In vitro, T cell clones recognized and killed melanoma cells in an antigen-specific manner. Thus, CpG 7909 is an efficient vaccine adjuvant that promotes strong antigen-specific CD8+ T cell responses in humans.

  17. Carpal tunnel syndrome in inherited neuropathies: A retrospective survey. (United States)

    Panosyan, Francis B; Kirk, Callyn A; Marking, Devon; Reilly, Mary M; Scherer, Steven S; Shy, Michael E; Herrmann, David N


    This study evaluates carpal tunnel syndrome (CTS) symptom severity, functional status, and outcome of CTS therapies in patients with inherited neuropathies. Validated questionnaires were used to compare symptom severity and functional status in patients with and without a diagnosis of CTS and a diagnosis of an inherited neuropathy. 309 patients with inherited neuropathies participated in this study. The CTS symptom severity score (SSS) was found to be the most useful tool in assessing CTS severity in patients with inherited neuropathy. Splint therapy and surgery were associated with significant improvement in carpal tunnel symptoms as measured through the SSS. This study provides insight into the assessment of CTS symptom severity and patient-reported outcomes to CTS therapy in individuals with inherited neuropathies. The SSS appears useful for evaluation of CTS symptoms and patient-reported outcomes following CTS interventions in individuals with inherited neuropathies. Muscle Nerve, 2017. © 2017 Wiley Periodicals, Inc.

  18. Paternal inheritance of mitochondrial DNA in the sheep (Ovine aries)

    Institute of Scientific and Technical Information of China (English)


    Paternal inheritance of mitochondria DNA in sheep was discovered by examination of 152 sheep from 38 hybrid families for mtDNA D-loop polymorphisms using PCR-RFLP, amplification of repeated sequence somain, and PCR-SSCP of the D-loop 5′ end region of a 253 bp fragment. Our findings have provided the first evidence of paternal inheritance of mtDNA in sheep and possible mechanisms of paternal inheritance were discussed.

  19. Induction of systemic TH1-like innate immunity in normal volunteers following subcutaneous but not intravenous administration of CPG 7909, a synthetic B-class CpG oligodeoxynucleotide TLR9 agonist. (United States)

    Krieg, Arthur M; Efler, Susan M; Wittpoth, Michael; Al Adhami, Mohammed J; Davis, Heather L


    Subcutaneous injection of normal human volunteers with a B-class CpG oligodeoxynucleotide (ODN) TLR9 agonist, CPG 7909, induced a TH1-like pattern of systemic innate immune activation manifested by expression of IL-6, IL-12p40, IFN-alpha, and IFN-inducible chemokines. Serum IP-10 was found to be the most sensitive assay for subcutaneous CPG 7909 stimulation; its level was significantly increased in all subjects at all dose levels, including the lowest tested dose of just 0.0025 mg/kg. This pattern of chemokine and cytokine induction was markedly different from that previously reported to be induced by TLR9 stimulation in rodents, most likely reflecting species-specific differences in the cell types expressing TLR9. Subcutaneous CPG 7909 injection induced transient shifts in blood neutrophils, lymphocytes, and monocytes, consistent with the increased chemokine expression. Levels of acute phase reactants such as C-reactive protein were also increased. A second subcutaneous CPG 7909 injection administered 2 weeks after the first elicited similar immune responses, showing little or no tolerance to the effects of repeated in vivo TLR9 stimulation. Subjects developed dose-dependent transient injection site reactions and flu-like symptoms but otherwise tolerated injection well, with no evidence of organ toxicity or systemic autoimmunity. The activation of innate immunity was dependent on the route of ODN administration, since intravenous injection caused no such effects. These studies indicate that in vivo activation of TLR9 by subcutaneous administration of CPG 7909 could be a well-tolerated immunotherapeutic approach for induction of TH1 innate immune activation.

  20. Inferring clonal structure in HTLV-1-infected individuals: towards bridging the gap between analysis and visualization. (United States)

    Farmanbar, Amir; Firouzi, Sanaz; Makałowski, Wojciech; Iwanaga, Masako; Uchimaru, Kaoru; Utsunomiya, Atae; Watanabe, Toshiki; Nakai, Kenta


    Human T cell leukemia virus type 1 (HTLV-1) causes adult T cell leukemia (ATL) in a proportion of infected individuals after a long latency period. Development of ATL is a multistep clonal process that can be investigated by monitoring the clonal expansion of HTLV-1-infected cells by isolation of provirus integration sites. The clonal composition (size, number, and combinations of clones) during the latency period in a given infected individual has not been clearly elucidated. We used high-throughput sequencing technology coupled with a tag system for isolating integration sites and measuring clone sizes from 60 clinical samples. We assessed the role of clonality and clone size dynamics in ATL onset by modeling data from high-throughput monitoring of HTLV-1 integration sites using single- and multiple-time-point samples. From four size categories analyzed, we found that big clones (B; 513-2048 infected cells) and very big clones (VB; >2048 infected cells) had prognostic value. No sample harbored two or more VB clones or three or more B clones. We examined the role of clone size, clone combination, and the number of integration sites in the prognosis of infected individuals. We found a moderate reverse correlation between the total number of clones and the size of the largest clone. We devised a data-driven model that allows intuitive representation of clonal composition. This integration site-based clonality tree model represents the complexity of clonality and provides a global view of clonality data that facilitates the analysis, interpretation, understanding, and visualization of the behavior of clones on inter- and intra-individual scales. It is fully data-driven, intuitively depicts the clonality patterns of HTLV-1-infected individuals and can assist in early risk assessment of ATL onset by reflecting the prognosis of infected individuals. This model should assist in assimilating information on clonal composition and understanding clonal expansion in HTLV-1

  1. Emulating Multiple Inheritance in Fortran 2003/2008

    Directory of Open Access Journals (Sweden)

    Karla Morris


    in Fortran 2003. The design unleashes the power of the associated class relationships for modeling complicated data structures yet avoids the ambiguities that plague some multiple inheritance scenarios.

  2. Inheritance Hierarchy Based Reuse & Reusability Metrics in OOSD

    Directory of Open Access Journals (Sweden)

    Nasib S. Gill,


    Full Text Available Reuse and reusability are two major aspects in object oriented software which can be measured from inheritance hierarchy. Reusability is the prerequisite of reuse but both may or may not bemeasured using same metric. This paper characterizes metrics of reuse and reusability in Object Oriented Software Development (OOSD. Reuse metrics compute the extent to which classes have been reused and reusability metrics computes the extent to which classes can be reused. In this paper five new metrics namely- Breadth of Inheritance Tree (BIT, Method Reuse Per Inheritance Relation (MRPIR,Attribute Reuse Per Inheritance Relation (ARPIR, Generality of Class (GC and Reuse Probability (RP have been proposed. These metrics help to evaluate reuse and reusability of object oriented software.Four extensively validated existing object oriented metrics, namely- Depth of Inheritance Tree (DIT, Number of Children (NOC, Method Inheritance Factor (MIF and Attribute Inheritance Factor (AIFhave been selected and investigated for comparison with proposed metrics. All metrics can be computed from inheritance hierarchies and classified according to their characteristics. Further, metrics areevaluated against a case study. These metrics are helpful in comparing alternative inheritance hierarchies at design time to select best alternative, so that the development time and cost can be reduced.

  3. Quantum-inspired immune clonal algorithm for global optimization. (United States)

    Jiao, Licheng; Li, Yangyang; Gong, Maoguo; Zhang, Xiangrong


    Based on the concepts and principles of quantum computing, a novel immune clonal algorithm, called a quantum-inspired immune clonal algorithm (QICA), is proposed to deal with the problem of global optimization. In QICA, the antibody is proliferated and divided into a set of subpopulation groups. The antibodies in a subpopulation group are represented by multistate gene quantum bits. In the antibody's updating, the general quantum rotation gate strategy and the dynamic adjusting angle mechanism are applied to accelerate convergence. The quantum not gate is used to realize quantum mutation to avoid premature convergences. The proposed quantum recombination realizes the information communication between subpopulation groups to improve the search efficiency. Theoretical analysis proves that QICA converges to the global optimum. In the first part of the experiments, 10 unconstrained and 13 constrained benchmark functions are used to test the performance of QICA. The results show that QICA performs much better than the other improved genetic algorithms in terms of the quality of solution and computational cost. In the second part of the experiments, QICA is applied to a practical problem (i.e., multiuser detection in direct-sequence code-division multiple-access systems) with a satisfying result.

  4. Clonal population structure of Colombian sylvatic Trypanosoma cruzi. (United States)

    Márquez, E; Arcos-Burgos, M; Triana, O; Moreno, J; Jaramillo, N


    Isoenzyme variability and evidence of genetic exchange were evaluated in 75 wild stocks of Trypanosoma cruzi obtained from different hosts from 5 geographical regions within the endemic area in Colombia. Cluster analysis of genetic variability was attempted. Thirty-three multilocus enzyme genotypes (clonets) were identified from 75 stocks, 27 of which clustered with zymodeme Z1 and 6 with zymodeme Z3. Two stocks isolated from human infections showed the potential risk to rural communities in Colombia. The stocks exhibited departures from Hardy-Weinberg expectations, including both fixed heterozygote and fixed homozygote demes, where both segregation and recombination were absent. To inspect for population subdivision that might falsely imply clonality in these stocks, Wright's F statistics were calculated. Theta values (Fst) were significantly different from 0 when 33 clonets, 27 Z1-like clonets, and 5 geographical subpopulations were compared; thus, a significant amount of divergence has occurred between and within them. In addition, linkage disequilibrium was detected for most possible pairwise comparisons of loci. In conclusion, the above results all support a scenario of long-term clonal evolution in Colombian sylvatic T. cruzi populations.

  5. Preventing clonal evolutionary processes in cancer: Insights from mathematical models. (United States)

    Rodriguez-Brenes, Ignacio A; Wodarz, Dominik


    Clonal evolutionary processes can drive pathogenesis in human diseases, with cancer being a prominent example. To prevent or treat cancer, mechanisms that can potentially interfere with clonal evolutionary processes need to be understood better. Mathematical modeling is an important research tool that plays an ever-increasing role in cancer research. This paper discusses how mathematical models can be useful to gain insights into mechanisms that can prevent disease initiation, help analyze treatment responses, and aid in the design of treatment strategies to combat the emergence of drug-resistant cells. The discussion will be done in the context of specific examples. Among defense mechanisms, we explore how replicative limits and cellular senescence induced by telomere shortening can influence the emergence and evolution of tumors. Among treatment approaches, we consider the targeted treatment of chronic lymphocytic leukemia (CLL) with tyrosine kinase inhibitors. We illustrate how basic evolutionary mathematical models have the potential to make patient-specific predictions about disease and treatment outcome, and argue that evolutionary models could become important clinical tools in the field of personalized medicine.

  6. Streptococcus mutans clonal variation revealed by multilocus sequence typing. (United States)

    Nakano, Kazuhiko; Lapirattanakul, Jinthana; Nomura, Ryota; Nemoto, Hirotoshi; Alaluusua, Satu; Grönroos, Lisa; Vaara, Martti; Hamada, Shigeyuki; Ooshima, Takashi; Nakagawa, Ichiro


    Streptococcus mutans is the major pathogen of dental caries, a biofilm-dependent infectious disease, and occasionally causes infective endocarditis. S. mutans strains have been classified into four serotypes (c, e, f, and k). However, little is known about the S. mutans population, including the clonal relationships among strains of S. mutans, in relation to the particular clones that cause systemic diseases. To address this issue, we have developed a multilocus sequence typing (MLST) scheme for S. mutans. Eight housekeeping gene fragments were sequenced from each of 102 S. mutans isolates collected from the four serotypes in Japan and Finland. Between 14 and 23 alleles per locus were identified, allowing us theoretically to distinguish more than 1.2 x 10(10) sequence types. We identified 92 sequence types in these 102 isolates, indicating that S. mutans contains a diverse population. Whereas serotype c strains were widely distributed in the dendrogram, serotype e, f, and k strains were differentiated into clonal complexes. Therefore, we conclude that the ancestral strain of S. mutans was serotype c. No geographic specificity was identified. However, the distribution of the collagen-binding protein gene (cnm) and direct evidence of mother-to-child transmission were clearly evident. In conclusion, the superior discriminatory capacity of this MLST scheme for S. mutans may have important practical implications.

  7. The Use of Auxin Quantification for Understanding Clonal Tree Propagation

    Directory of Open Access Journals (Sweden)

    Carlos A. Stuepp


    Full Text Available Qualitative and quantitative hormone analyses have been essential for understanding the metabolic, physiological, and morphological processes that are influenced by plant hormones. Auxins are key hormones in the control of many aspects of plant growth and development and their endogenous levels are considered critical in the process of adventitious root induction. Exogenous auxins are used extensively in the clonal propagation of tree species by cuttings or tissue culture. Understanding of auxin effects has advanced with the development of increasingly accurate methods for auxin quantification. However, auxin analysis has been challenging because auxins typically occur at low concentrations, while compounds that interfere with their detection often occur at high concentrations, in plant tissues. Interference from other compounds has been addressed by extensive purification of plant extracts prior to auxin analysis, although this means that quantification methods have been limited by their expense. This review explores the extraction, purification, and quantification of auxins and the application of these techniques in developing improved methods for the clonal propagation of forestry trees.


    Directory of Open Access Journals (Sweden)

    Elena Brînduse


    Full Text Available Four elite clonal accessions of Vitis vinifera L., Chasselas doré variety were identified in a very old plantation, of 110 years, located in Valea Cãlugãreascã, on the St. Nicolas Monastery vineyard. The vines, grafted on the SO4 (Selection Oppenheim 4 rootstock, were planted in 2007 in the germplasm collection belonging to the Research and Development Institute for Viticulture and Enology, Valea Cãlugãreascã. The present study aimed to evaluate these elite clonal accessions from ampelographic point of view, in comparison with Chasselas doré variety. Ampelographic characterization of genotypes was performed according to the descriptors ampelographic methodology, based on the specifications made in the OIV Descriptor List for Grape Varieties and Vitis species, Second Edition (2009. The shoot tips descriptions were made when they were approximately 10 to 30 cm in height and, in this stage, also, the first four distal leaves of young leaves were evaluated. Mature leaf descriptions were carried out between berry set and veraison. The clusters and berry characteristics were evaluated at maturity and woody shoots were analyzed after fall of the leaves. Ampelographic characterization was performed based on 59 descriptors, of which 43 for morphological characters and 16 for agro-biological attributes.

  9. Rapid contemporary evolution and clonal food web dynamics. (United States)

    Jones, Laura E; Becks, Lutz; Ellner, Stephen P; Hairston, Nelson G; Yoshida, Takehito; Fussmann, Gregor F


    Character evolution that affects ecological community interactions often occurs contemporaneously with temporal changes in population size, potentially altering the very nature of those dynamics. Such eco-evolutionary processes may be most readily explored in systems with short generations and simple genetics. Asexual and cyclically parthenogenetic organisms such as microalgae, cladocerans and rotifers, which frequently dominate freshwater plankton communities, meet these requirements. Multiple clonal lines can coexist within each species over extended periods, until either fixation occurs or a sexual phase reshuffles the genetic material. When clones differ in traits affecting interspecific interactions, within-species clonal dynamics can have major effects on the population dynamics. We first consider a simple predator-prey system with two prey genotypes, parametrized with data from a well-studied experimental system, and explore how the extent of differences in defence against predation within the prey population determine dynamic stability versus instability of the system. We then explore how increased potential for evolution affects the community dynamics in a more general community model with multiple predator and multiple prey genotypes. These examples illustrate how microevolutionary 'details' that enhance or limit the potential for heritable phenotypic change can have significant effects on contemporaneous community-level dynamics and the persistence and coexistence of species.

  10. Escherichia coli ST131, an Intriguing Clonal Group (United States)

    Bertrand, Xavier; Madec, Jean-Yves


    SUMMARY In 2008, a previously unknown Escherichia coli clonal group, sequence type 131 (ST131), was identified on three continents. Today, ST131 is the predominant E. coli lineage among extraintestinal pathogenic E. coli (ExPEC) isolates worldwide. Retrospective studies have suggested that it may originally have risen to prominence as early as 2003. Unlike other classical group B2 ExPEC isolates, ST131 isolates are commonly reported to produce extended-spectrum β-lactamases, such as CTX-M-15, and almost all are resistant to fluoroquinolones. Moreover, ST131 E. coli isolates are considered to be truly pathogenic, due to the spectrum of infections they cause in both community and hospital settings and the large number of virulence-associated genes they contain. ST131 isolates therefore seem to contradict the widely held view that high levels of antimicrobial resistance are necessarily associated with a fitness cost leading to a decrease in pathogenesis. Six years after the first description of E. coli ST131, this review outlines the principal traits of ST131 clonal group isolates, based on the growing body of published data, and highlights what is currently known and what we need to find out to provide public health authorities with better information to help combat ST131. PMID:24982321

  11. Molecular mechanisms for protein-encoded inheritance. (United States)

    Wiltzius, Jed J W; Landau, Meytal; Nelson, Rebecca; Sawaya, Michael R; Apostol, Marcin I; Goldschmidt, Lukasz; Soriaga, Angela B; Cascio, Duilio; Rajashankar, Kanagalaghatta; Eisenberg, David


    In prion inheritance and transmission, strains are phenotypic variants encoded by protein 'conformations'. However, it is unclear how a protein conformation can be stable enough to endure transmission between cells or organisms. Here we describe new polymorphic crystal structures of segments of prion and other amyloid proteins, which offer two structural mechanisms for the encoding of prion strains. In packing polymorphism, prion strains are encoded by alternative packing arrangements (polymorphs) of beta-sheets formed by the same segment of a protein; in segmental polymorphism, prion strains are encoded by distinct beta-sheets built from different segments of a protein. Both forms of polymorphism can produce enduring conformations capable of encoding strains. These molecular mechanisms for transfer of protein-encoded information into prion strains share features with the familiar mechanism for transfer of nucleic acid-encoded information into microbial strains, including sequence specificity and recognition by noncovalent bonds.

  12. Mitochondrial genome function and maternal inheritance. (United States)

    Allen, John F; de Paula, Wilson B M


    The persistence of mtDNA to encode a small subset of mitochondrial proteins reflects the selective advantage of co-location of key respiratory chain subunit genes with their gene products. The disadvantage of this co-location is exposure of mtDNA to mutagenic ROS (reactive oxygen species), which are by-products of aerobic respiration. The resulting 'vicious circle' of mitochondrial mutation has been proposed to underlie aging and its associated degenerative diseases. Recent evidence is consistent with the hypothesis that oocyte mitochondria escape the aging process by acting as quiescent genetic templates, transcriptionally and bioenergetically repressed. Transmission of unexpressed mtDNA in the female germline is considered as a reason for the existence of separate sexes, i.e. male and female. Maternal inheritance then circumvents incremental accumulation of age-related disease in each new generation.

  13. Dominantly inherited isolated hyperparathyroidism: a syndromic association?

    Energy Technology Data Exchange (ETDEWEB)

    Kozlowski, K. [Department of Radiology, Royal Alexandra Hospital for Children, Sydney (Australia)]|[Department of Radiology, New Children`s Hospital, PO Box 3515, Parramatta, NSW 2124 (Australia); Czerminska-Kowalska, A. [Department of Radiology, Children`s Memorial Health Institute, Warsaw (Poland); Kulczycka, H.; Rowinska, E.; Pronicka, E. [Department of Metabolism, Children`s Memorial Health Institute, Warsaw (Poland)


    Dominantly inherited isolated hyperparathyroidism (DIIH) is rare in childhood. It may be the first biochemical abnormality in the multiple endocrine neoplasia type I (MEN I) and type II (MEN II) syndromes. Its clinical course is usually asymptomatic or of low morbidity. Radiographic examination is most often normal. We describe six members of a family with distinctive phenotype and DIIH. Limited systemic symptoms and severe radiographic osteitis fibrosa cystica were further unusual features in this family. The diagnosis of DIIH was made only after a 9-year-old girl developed hypercalcaemic crisis after a pathological femoral fracture. Distinctive phenotype, unusual clinical course and unparalleled radiographic changes suggest a not yet described syndromic association. (orig.) With 7 figs., 3 tabs., 23 refs.

  14. Inherited renal tubular defects with hypokalemia

    Directory of Open Access Journals (Sweden)

    Muthukrishnan J


    Full Text Available Bartter′s and Gitelman′s syndrome are two ends of a spectrum of inherited renal tubular disorders that present with hypokalemic metabolic alkalosis of varying severity. Clinical features and associated calcium and magnesium ion abnormalities are used to diagnose these cases after excluding other commoner causes. We report on two cases, the first being a young boy, born of pregnancy complicated by polyhydramnios, who had classical dysmorphic features, polyuria, hypokalemia and hypercalciuria and was diagnosed as having Bartter′s syndrome. The second patient is a lady who had recurrent tetany as the only manifestation of Gitelman′s syndrome, which is an unusual presentation. Potassium replacement with supplementation of other deficient ions led to satisfactory clinical and biochemical response.

  15. Secret sharing scheme with inherited characteristic

    Institute of Scientific and Technical Information of China (English)

    Ye Zhenjun; Meng Fanzhen


    To assure the shareholders can look for their "legal" attorneys to renew the secret, once the secret sharing scheme is initialized, a secret sharing scheme with inherited characteristic is constructed. In this scheme, each shareholder can produce a new share by his algorithm, which is equivalent to the primary one. Together with other shares, the primary secret can be renewed. Since this scheme is constructed not by replacing the primary share with a new share produced by the dealer in his primitive secret sharing scheme, so no matter how much shares the shareholder produces, these shares can not be gathered together to renew the secret in this scheme. Compared with the existing secret sharing schemes, this scheme provides more agility for the shareholders by investing each of them a function but not affect its security.

  16. Molecular mechanisms for protein-encoded inheritance

    Energy Technology Data Exchange (ETDEWEB)

    Wiltzius, Jed J.W.; Landau, Meytal; Nelson, Rebecca; Sawaya, Michael R.; Apostol, Marcin I.; Goldschmidt, Lukasz; Soriaga, Angela B.; Cascio, Duilio; Rajashankar, Kanagalaghatta; Eisenberg, David; (Cornell); (HHMI)


    In prion inheritance and transmission, strains are phenotypic variants encoded by protein 'conformations'. However, it is unclear how a protein conformation can be stable enough to endure transmission between cells or organisms. Here we describe new polymorphic crystal structures of segments of prion and other amyloid proteins, which offer two structural mechanisms for the encoding of prion strains. In packing polymorphism, prion strains are encoded by alternative packing arrangements (polymorphs) of {beta}-sheets formed by the same segment of a protein; in segmental polymorphism, prion strains are encoded by distinct {beta}-sheets built from different segments of a protein. Both forms of polymorphism can produce enduring conformations capable of encoding strains. These molecular mechanisms for transfer of protein-encoded information into prion strains share features with the familiar mechanism for transfer of nucleic acid-encoded information into microbial strains, including sequence specificity and recognition by noncovalent bonds.

  17. Using default inheritance to describe LTAG

    CERN Document Server

    Evans, R; Weir, D; Evans, Roger; Gazdar, Gerald; Weir, David


    We present the results of an investigation into how the set of elementary trees of a Lexicalized Tree Adjoining Grammar can be represented in the lexical knowledge representation language DATR (Evans & Gazdar 1989a,b). The LTAG under consideration is based on the one described in Abeille et al. (1990). Our approach is similar to that of Vijay-Shanker & Schabes (1992) in that we formulate an inheritance hierarchy that efficiently encodes the elementary trees. However, rather than creating a new representation formalism for this task, we employ techniques of established utility in other lexically-oriented frameworks. In particular, we show how DATR's default mechanism can be used to eliminate the need for a non-immediate dominance relation in the descriptions of the surface LTAG entries. This allows us to embed the tree structures in the feature theory in a manner reminiscent of HPSG subcategorisation frames, and hence express lexical rules as relations over feature structures.

  18. Chloroplast DNA methylation and inheritance in Chlamydomonas (United States)

    Umen, James G.; Goodenough, Ursula W.


    When Chlamydomonas reinhardtii cells mate, a zygotic maturation program is activated, part of which leads to destruction of chloroplast DNA (cpDNA) from the mating type minus (mt−) parent, and, therefore, to uniparental inheritance of mating type plus (mt+) cpDNA. A long-standing model that explains the selective destruction of mt− cpDNA in zygotes invokes a methylation-restriction system. We tested this model by using the potent methylation inhibitor 5-aza-2‘-deoxycytidine (5adc) to hypomethylate parental cpDNA and found that the pattern of cpDNA inheritance is altered by 5adc in a manner that is consistent with the model. Surprisingly, however, hypomethylated mt+ cpDNA is not destroyed in zygotes as the methylation-restriction model predicts it should be. Destruction of mt− cpDNA is also unaffected when the parental mt+ cpDNA is hypomethylated. Instead, loss of methylation affects the relative rates of replication of residual mt− cpDNA and mt+ cpDNA in germinating zygotes. The mode of action for 5adc on cpDNA replication in germinating zygotes may be via hypomethylation of mt+ cpDNA, but is also consistent with its action as a DNA-damaging agent. Interestingly, 5adc causes reduced cpDNA replication only in germinating zygotes, not in vegetatively grown cells, indicating that cpDNA replication is qualitatively different in these two stages of the life cycle. Our results demonstrate that methylation is not necessary for protection of the mt+ cpDNA in early zygotes and uncover a novel stage of the Chlamydomonas life cycle when replication of cpDNA is highly susceptible to perturbation. Our data support a model in which differential cpDNA replication in germinating zygotes is used as a mechanism to selectively amplify intact and properly methylated cpDNA molecules. PMID:11581163

  19. Development of a subunit vaccine containing recombinant Riemerella anatipestifer outer membrane protein A and CpG ODN adjuvant. (United States)

    Chu, Chun-Yen; Liu, Chia-Hui; Liou, Jhong-Jie; Lee, Jai-Wei; Cheng, Li-Ting


    Riemerella anatipestifer, a Gram-negative bacillus, causes septicemia that can result in high mortality for ducklings. In this study, we evaluated the immune response and protective efficacy provided by a subunit vaccine containing recombinant outer membrane protein A (rOmpA) and plasmid constructs containing CpG oligodeoxynucleotides (ODN). Results showed that CpG ODN enhanced both humoral and cell-mediated immunity elicited by rOmpA as early as two weeks after primary immunization. When compared to ducks immunized with rOmpA, ducks immunized with rOmpA+CpG ODN showed higher levels (pvaccine reduced the pathological score by 90% in comparison with the saline control. In conclusion, our study found that CpG ODN can enhance both humoral and cellular immunity elicited by a rOmpA vaccine. The rOmpA+CpG ODN vaccine can be further developed as a subunit vaccine against R. anatipestifer.

  20. MPT-51/CpG DNA vaccine protects mice against Mycobacterium tuberculosis. (United States)

    Silva, Bruna Daniella de Souza; da Silva, Ediane Batista; do Nascimento, Ivan Pereira; Dos Reis, Michelle Cristina Guerreiro; Kipnis, André; Junqueira-Kipnis, Ana Paula


    Tuberculosis (TB) is a severe infectious disease that kills approximately two million people worldwide every year. Because BCG protection is variable and does not protects adults, there is a great need for a new vaccine against TB that does not represent a risk for immunocompromised patients and that is also capable of protecting adult individuals. MPT-51 is a protein found in the genome of mycobacteria and binds to the fibronectin of the extracellular matrix, which may have a role in host tissue attachment and virulence. In order to test the usefulness of MPT-51 as a subunit vaccine, BALB/c were vaccinated and challenged with Mycobacterium tuberculosis. The infection of BALB/c with M. tuberculosis increased the number of IFN-gamma(+) T lymphocytes specific to MPT-51 in the spleen and lungs. Inoculation with rMPT-51/FIA and with rMPT-51/CpG DNA in non-infected BALB/c increased the amounts of IFN-gamma(+) T lymphocytes. Inoculation with rMPT-51/FIA also induced a humoral response specific to MPT-51. CFU counts of lung tissues done 60 days after infection showed a reduction of about 2 log in the bacteria load in the group of animals inoculated with rMPT-51/CpG DNA. These results make MPT-51 a valuable component to be further evaluated in the development of other subunit vaccines.

  1. FPGA implementation of a configurable neuromorphic CPG-based locomotion controller. (United States)

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


    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.

  2. Focussing reduced representation CpG sequencing through judicious restriction enzyme choice. (United States)

    Kirschner, Sophie A; Hunewald, Oliver; Mériaux, Sophie B; Brunnhoefer, Regina; Muller, Claude P; Turner, Jonathan D


    Current restriction enzyme based reduced representation methylation analyses aim for limited, but unbiased, methylome coverage. As the current best estimate suggests that only ~20% of CpGs are dynamically regulated, we characterised the CpG and genomic context surrounding all suitable restriction enzyme sites to identify those that were located in regions rich in dynamically methylated CpGs. The restriction-site distributions for MspI, BstUI, and HhaI were non-random. CpGs in CGI and shelf+shore could be enriched, particularly in gene bodies for all genomic regions, promoters (TSS1500, TSS200), intra- (1st exon, gene body, 3'UTR, 5'UTR) and inter-genic regions. HpyCH4IV enriched CpG elements in the open sea for all genomic elements. Judicious restriction enzyme choice improves the focus of reduced representation approaches by avoiding the monopolization of read coverage by genomic regions that are irrelevant, unwanted or difficult to map, and only sequencing the most informative fraction of CpGs.

  3. Determining coding CpG islands by identifying regions significant for pattern statistics on Markov chains. (United States)

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


    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.

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

    Directory of Open Access Journals (Sweden)

    Steven M. Barlow


    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.

  5. Nanopores suggest a negligible influence of CpG methylation on nucleosome packaging and stability. (United States)

    Langecker, Martin; Ivankin, Andrey; Carson, Spencer; Kinney, Shannon R M; Simmel, Friedrich C; Wanunu, Meni


    Nucleosomes are the fundamental repeating units of chromatin, and dynamic regulation of their positioning along DNA governs gene accessibility in eukaryotes. Although epigenetic factors have been shown to influence nucleosome structure and dynamics, the impact of DNA methylation on nucleosome packaging remains controversial. Further, all measurements to date have been carried out under zero-force conditions. In this paper, we present the first automated force measurements that probe the impact of CpG DNA methylation on nucleosome stability. In solid-state nanopore force spectroscopy, a nucleosomal DNA tail is captured into a pore and pulled on with a time-varying electrophoretic force until unraveling is detected. This is automatically repeated for hundreds of nucleosomes, yielding statistics of nucleosome lifetime vs electrophoretic force. The force geometry, which is similar to displacement forces exerted by DNA polymerases and helicases, reveals that nucleosome stability is sensitive to DNA sequence yet insensitive to CpG methylation. Our label-free method provides high-throughput data that favorably compares with other force spectroscopy experiments and is suitable for studying a variety of DNA-protein complexes.

  6. The clustering of CpG islands may constitute an important determinant of the 3D organization of interphase chromosomes. (United States)

    Gushchanskaya, Ekaterina S; Artemov, Artem V; Ulyanov, Sergey V; Logacheva, Maria D; Penin, Aleksey A; Kotova, Elena S; Akopov, Sergey B; Nikolaev, Lev G; Iarovaia, Olga V; Sverdlov, Eugene D; Gavrilov, Alexey A; Razin, Sergey V


    We used the 4C-Seq technique to characterize the genome-wide patterns of spatial contacts of several CpG islands located on chromosome 14 in cultured chicken lymphoid and erythroid cells. We observed a clear tendency for the spatial clustering of CpG islands present on the same and different chromosomes, regardless of the presence or absence of promoters within these CpG islands. Accordingly, we observed preferential spatial contacts between Sp1 binding motifs and other GC-rich genomic elements, including the DNA sequence motifs capable of forming G-quadruplexes. However, an anchor placed in a gene/CpG island-poor area formed spatial contacts with other gene/CpG island-poor areas on chromosome 14 and other chromosomes. These results corroborate the two-compartment model of the spatial organization of interphase chromosomes and suggest that the clustering of CpG islands constitutes an important determinant of the 3D organization of the eukaryotic genome in the cell nucleus. Using the ChIP-Seq technique, we mapped the genome-wide CTCF deposition sites in the chicken lymphoid and erythroid cells that were used for the 4C analysis. We observed a good correlation between the density of CTCF deposition sites and the level of 4C signals for the anchors located in CpG islands but not for an anchor located in a gene desert. It is thus possible that CTCF contributes to the clustering of CpG islands observed in our experiments.

  7. Effects of Light on the Growth and Clonal Reproduction of Ligularia virgaurea

    Institute of Scientific and Technical Information of China (English)

    Man-Tang Wang; Zhi-Gang Zhao; Guo-Zhen Du; Yan-Long He


    Ligularia virgaurea is a perennial herb that is widely distributed in the alpine meadow on the eastern Qinghai-Tibet plateau.We investigated the patterns of growth and reproduction of L.virgaurea under two contrasting levels of light conditions for two continuous growing seasons.Our results showed that the light affects on the maximum relative growth rate,the shoot weight ratio and the root weight ratio differed between the two growing seasons.L.virgaurea reproduced initially through rhizome in the second growing season,rather than sexual reproduction.The proportion of genets with clonal reproduction decreased under shaded conditions.A minimum genet size should be attained for clonal reproduction to begin under the shaded conditions.There was a positive linear relationship between clonal reproduction and genet size.Light level affected the allocation of total biomass to clonal structures,with less allocation under the full natural irradiance than under the shaded conditions.There seemed to be a trade-off between vegetative growth and clonal reproduction under the full natural irradiance,in terms of smaller relative growth rates of genets with clonal reproduction than those without clonal reproduction.L.virgaurea emphasized clonal reproduction under the full natural irradiance,while the plant emphasized vegetative growth under the shaded conditions.

  8. African 2, a clonal complex of Mycobacterium bovis epidemiologically important in East Africa.

    NARCIS (Netherlands)

    Berg, S.; Garcia-Pelayo, M.C.; Muller, B.; Hailu, E.; Asiimwe, B.; Kremer, K.; Dale, J.; Boniotti, M.B.; Rodriguez, S.; Hilty, M.; Rigouts, L.; Firdessa, R.; Machado, A.; Mucavele, C.; Ngandolo, B.N.; Bruchfeld, J.; Boschiroli, L.; Muller, A.; Sahraoui, N.; Pacciarini, M.; Cadmus, S.; Joloba, M.; Soolingen, D. van; Michel, A.L.; Djonne, B.; Aranaz, A.; Zinsstag, J.; Helden, P. van; Portaels, F.; Kazwala, R.; Kallenius, G.; Hewinson, R.G.; Aseffa, A.; Gordon, S.V.; Smith, N.H.


    We have identified a clonal complex of Mycobacterium bovis isolated at high frequency from cattle in Uganda, Burundi, Tanzania, and Ethiopia. We have named this related group of M. bovis strains the African 2 (Af2) clonal complex of M. bovis. Af2 strains are defined by a specific chromosomal deletio

  9. Genotype-by-temperature interactions may help to maintain clonal diversity in asterionella formosa (Bacillariophyceae)

    NARCIS (Netherlands)

    Gsell, A.S.; Domis, L.N.D.; Przytulska-Bartosiewicz, A.; Mooij, W.M.; Donk, van E.; Ibelings, B.W.


    Marine and freshwater phytoplankton populations often show large clonal diversity, which is in disagreement with clonal selection of the most vigorous genotype(s). Temporal fluctuation in selection pressures in variable environments is a leading explanation for maintenance of such genetic diversity.

  10. Erasure of CpG methylation in Arabidopsis alters patterns of histone H3 methylation in heterochromatin

    DEFF Research Database (Denmark)

    Tariq, M.; Saze, H.; Probst, A.;


    DNA methylation to histone methylation, however, is less understood. Its recent examination in Arabidopsis with a partial loss of function in DNA methyltransferase 1 (responsible for maintenance of CpG methylation) yielded conflicting results. Here we report that complete removal of CpG methylation...... in an Arabidopsis mutant null for DNA maintenance methyltransferase results in a clear loss of histone H3 methylation at lysine 9 in heterochromatin and also at heterochromatic loci that remain transcriptionally silent. Surprisingly, these dramatic alterations are not reflected in heterochromatin relaxation....

  11. Uncovering the Number and Clonal Dynamics of Mesp1 Progenitors during Heart Morphogenesis

    Directory of Open Access Journals (Sweden)

    Samira Chabab


    Full Text Available The heart arises from distinct sources of cardiac progenitors that independently express Mesp1 during gastrulation. The precise number of Mesp1 progenitors that are specified during the early stage of gastrulation, and their clonal behavior during heart morphogenesis, is currently unknown. Here, we used clonal and mosaic tracing of Mesp1-expressing cells combined with quantitative biophysical analysis of the clonal data to define the number of cardiac progenitors and their mode of growth during heart development. Our data indicate that the myocardial layer of the heart derive from ∼250 Mesp1-expressing cardiac progenitors born during gastrulation. Despite arising at different time points and contributing to different heart regions, the temporally distinct cardiac progenitors present very similar clonal dynamics. These results provide insights into the number of cardiac progenitors and their mode of growth and open up avenues to decipher the clonal dynamics of progenitors in other organs and tissues.

  12. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade (United States)

    McGranahan, Nicholas; Furness, Andrew J. S.; Rosenthal, Rachel; Ramskov, Sofie; Lyngaa, Rikke; Saini, Sunil Kumar; Jamal-Hanjani, Mariam; Wilson, Gareth A.; Birkbak, Nicolai J.; Hiley, Crispin T.; Watkins, Thomas B. K.; Shafi, Seema; Murugaesu, Nirupa; Mitter, Richard; Akarca, Ayse U.; Linares, Joseph; Marafioti, Teresa; Henry, Jake Y.; Van Allen, Eliezer M.; Miao, Diana; Schilling, Bastian; Schadendorf, Dirk; Garraway, Levi A.; Makarov, Vladimir; Rizvi, Naiyer A.; Snyder, Alexandra; Hellmann, Matthew D.; Merghoub, Taha; Wolchok, Jedd D.; Shukla, Sachet A.; Wu, Catherine J.; Peggs, Karl S.; Chan, Timothy A.; Hadrup, Sine R.; Quezada, Sergio A.; Swanton, Charles


    As tumors grow, they acquire mutations, some of which create neoantigens that influence the response of patients to immune checkpoint inhibitors. We explored the impact of neoantigen intratumor heterogeneity (ITH) on antitumor immunity. Through integrated analysis of ITH and neoantigen burden, we demonstrate a relationship between clonal neoantigen burden and overall survival in primary lung adenocarcinomas. CD8+ tumor-infiltrating lymphocytes reactive to clonal neoantigens were identified in early-stage non–small cell lung cancer and expressed high levels of PD-1. Sensitivity to PD-1 and CTLA-4 blockade in patients with advanced NSCLC and melanoma was enhanced in tumors enriched for clonal neoantigens. T cells recognizing clonal neoantigens were detectable in patients with durable clinical benefit. Cytotoxic chemotherapy–induced subclonal neoantigens, contributing to an increased mutational load, were enriched in certain poor responders. These data suggest that neoantigen heterogeneity may influence immune surveillance and support therapeutic developments targeting clonal neoantigens. PMID:26940869

  13. SNP-based differentiation of Phytophthora infestans clonal lineages using locked nucleic acid probes and high resolution melt analysis (United States)

    Phytophthora infestans, the cause of the devastating late blight disease of potato and tomato, exhibits a clonal reproductive lifestyle in North America. Phenotypes such as fungicide sensitivity and host preference are conserved among individuals within clonal lineages, while substantial phenotypic ...

  14. Endothelial progenitor cells display clonal restriction in multiple myeloma

    Directory of Open Access Journals (Sweden)

    Dai Kezhi


    Full Text Available Abstract Background In multiple myeloma (MM, increased neoangiogenesis contributes to tumor growth and disease progression. Increased levels of endothelial progenitor cells (EPCs contribute to neoangiogenesis in MM, and, importantly, covary with disease activity and response to treatment. In order to understand the mechanisms responsible for increased EPC levels and neoangiogenic function in MM, we investigated whether these cells were clonal by determining X-chromosome inactivation (XCI patterns in female patients by a human androgen receptor assay (HUMARA. In addition, EPCs and bone marrow cells were studied for the presence of clonotypic immunoglobulin heavy-chain (IGH gene rearrangement, which indicates clonality in B cells; thus, its presence in EPCs would indicate a close genetic link between tumor cells in MM and endothelial cells that provide tumor neovascularization. Methods A total of twenty-three consecutive patients who had not received chemotherapy were studied. Screening in 18 patients found that 11 displayed allelic AR in peripheral blood mononuclear cells, and these patients were further studied for XCI patterns in EPCs and hair root cells by HUMARA. In 2 patients whose EPCs were clonal by HUMARA, and in an additional 5 new patients, EPCs were studied for IGH gene rearrangement using PCR with family-specific primers for IGH variable genes (VH. Results In 11 patients, analysis of EPCs by HUMARA revealed significant skewing (≥ 77% expression of a single allele in 64% (n = 7. In 4 of these patients, XCI skewing was extreme (≥ 90% expression of a single allele. In contrast, XCI in hair root cells was random. Furthermore, PCR amplification with VH primers resulted in amplification of the same product in EPCs and bone marrow cells in 71% (n = 5 of 7 patients, while no IGH rearrangement was found in EPCs from healthy controls. In addition, in patients with XCI skewing in EPCs, advanced age was associated with poorer clinical status

  15. 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 pa

  16. The foundation of extranuclear inheritance: plastid and mitochondrial genetics. (United States)

    Hagemann, Rudolf


    In 1909 two papers by Correns and by Baur published in volume 1 of Zeitschrift für induktive Abstammungs- und Vererbungslehre (now Molecular Genetics and Genomics) reported on the non-Mendelian inheritance of chlorophyll deficiencies. These papers, reporting the very first cases of extranuclear inheritance, laid the foundation for a new field: non-Mendelian or extranuclear genetics. Correns observed a purely maternal inheritance (in Mirabilis), whereas Baur found a biparental inheritance (in Pelargonium). Correns suspected the non-Mendelian factors in the cytoplasm, while Baur believed that the plastids carry these extranuclear factors. In the following years, Baur's hypothesis was proved to be correct. Baur subsequently developed the theory of plastid inheritance. In many genera the plastids are transmitted only uniparentally by the mother, while in a few genera there is a biparental plastid inheritance. Commonly there is random sorting of plastids during ontogenetic development. Renner and Schwemmle as well as geneticists in other countries added additional details to this theory. Pioneering studies on mitochondrial inheritance in yeast started in 1949 in the group of Ephrussi and Slonimski; respiration-deficient cells (petites in yeast, poky in Neurospora) were demonstrated to be due to mitochondrial mutations. Electron microscopical and biochemical studies (1962-1964) showed that plastids and mitochondria contain organelle-specific DNA molecules. These findings laid the molecular basis for the two branches of extranuclear inheritance: plastid and mitochondrial genetics.

  17. Proceedings of the Inheritance Workshop at ECOOP 2002

    DEFF Research Database (Denmark)


    The Inheritance Workshop at ECOOP 2002, which took place on Tuesday, 11 June, was the first ECOOP workshop focusing on inheritance after the successful workshops in 1991 and 1992. The workshop was intended as a forum for designers and implementers of object-oriented languages, and for software de...

  18. Inheritance study on the stable herbicide resistance of transgenic rice

    Institute of Scientific and Technical Information of China (English)

    WUMingguo; HUAZhihua; LINJianrong; XUERui; WANGXiaoling; HUANGDanian


    The transgene technology showed a potentiality in crop improvement such as disease and insect resistance, anti-adversity, and grain quality. The inheritance of bar gene for herbicide BASTA resistance in stable transformed rice lines was studied for an understanding of the foreign gene inheritance pattern.

  19. Statutory Law, Patriarchy and Inheritance: Home ownership among ...

    African Journals Online (AJOL)

    AFRicAn SOciOLOGicAL REviEW. Statutory Law, Patriarchy and ... marriage. Widows are only denied inheritance rights if they cannot afford to pay the mortgage rates. ... specifically handles inheritance and other family laws. This means that ...

  20. Population thinking and natural selection in dual-inheritance theory. (United States)

    Houkes, Wybo


    A deflationary perspective on theories of cultural evolution, in particular dual-inheritance theory, has recently been proposed by Lewens. On this 'pop-culture' analysis, dual-inheritance theorists apply population thinking to cultural phenomena, without claiming that cultural items evolve by natural selection. This paper argues against this pop-culture analysis of dual-inheritance theory. First, it focuses on recent dual-inheritance models of specific patterns of cultural change. These models exemplify population thinking without a commitment to natural selection of cultural items. There are grounds, however, for doubting the added explanatory value of the models in their disciplinary context-and thus grounds for engaging in other potentially explanatory projects based on dual-inheritance theory. One such project is suggested by advocates of the theory. Some of the motivational narratives that they offer can be interpreted as setting up an adaptationist project with regard to cumulative change in cultural items. We develop this interpretation here. On it, dual-inheritance theory features two interrelated selection processes, one on the level of genetically inherited learning mechanisms, another on the level of the cultural items transmitted through these mechanisms. This interpretation identifies a need for further modelling efforts, but also offers scope for enhancing the explanatory power of dual-inheritance theory.

  1. Manifestations and clinical impact of pediatric inherited thrombophilia. (United States)

    Klaassen, Irene L M; van Ommen, C Heleen; Middeldorp, Saskia


    The etiology of pediatric venous thromboembolic disease (VTE) is multifactorial, and in most children, 1 or more clinical risk factors are present. In addition, inherited thrombophilic disorders contribute to the development of pediatric VTE. In this review, the role of inherited thrombophilic disorders in the development of pediatric VTE, as well as the benefits and limitations of thrombophilia testing, will be discussed.

  2. Women's Inheritance Rights and Intergenerational Transmission of Resources in India (United States)

    Deininger, Klaus; Goyal, Aparajita; Nagarajan, Hari


    We use inheritance patterns over three generations of individuals to assess the impact of changes in the Hindu Succession Act that grant daughters equal coparcenary birth rights in joint family property that were denied to daughters in the past. We show that the amendment significantly increased daughters' likelihood to inherit land, but that…

  3. Women's Inheritance Rights and Intergenerational Transmission of Resources in India (United States)

    Deininger, Klaus; Goyal, Aparajita; Nagarajan, Hari


    We use inheritance patterns over three generations of individuals to assess the impact of changes in the Hindu Succession Act that grant daughters equal coparcenary birth rights in joint family property that were denied to daughters in the past. We show that the amendment significantly increased daughters' likelihood to inherit land, but that…

  4. Demographic consequences of greater clonal than sexual reproduction in Dicentra canadensis. (United States)

    Lin, Chia-Hua; Miriti, Maria N; Goodell, Karen


    Clonality is a widespread life history trait in flowering plants that may be essential for population persistence, especially in environments where sexual reproduction is unpredictable. Frequent clonal reproduction, however, could hinder sexual reproduction by spatially aggregating ramets that compete with seedlings and reduce inter-genet pollination. Nevertheless, the role of clonality in relation to variable sexual reproduction in population dynamics is often overlooked. We combined population matrix models and pollination experiments to compare the demographic contributions of clonal and sexual reproduction in three Dicentra canadensis populations, one in a well-forested landscape and two in isolated forest remnants. We constructed stage-based transition matrices from 3 years of census data to evaluate annual population growth rates, λ. We used loop analysis to evaluate the relative contribution of different reproductive pathways to λ. Despite strong temporal and spatial variation in seed set, populations generally showed stable growth rates. Although we detected some pollen limitation of seed set, manipulative pollination treatments did not affect population growth rates. Clonal reproduction contributed significantly more than sexual reproduction to population growth in the forest remnants. Only at the well-forested site did sexual reproduction contribute as much as clonal reproduction to population growth. Flowering plants were more likely to transition to a smaller size class with reduced reproductive potential in the following year than similarly sized nonflowering plants, suggesting energy trade-offs between sexual and clonal reproduction at the individual level. Seed production had negligible effects on growth and tuber production of individual plants. Our results demonstrate that clonal reproduction is vital for population persistence in a system where sexual reproduction is unpredictable. The bias toward clonality may be driven by low fitness returns

  5. Clonal distribution of pneumococcal serotype 19F isolates from Ghana

    DEFF Research Database (Denmark)

    Sparding, Nadja; Dayie, Nicholas Tete Kwaku Dzifa; Mills, Richael O.


    Streptococcus pneumoniae is a major cause of morbidity and mortality worldwide. Pneumococcal strains are classified according to their capsular polysaccharide and more than 90 different serotypes are currently known. In this project, three distinct groups of pneumococcal carriage isolates from...... Ghana were investigated; isolates from healthy children in Tamale and isolates from both healthy and children attending the outpatient department at a hospital in Accra. The isolates were previously identified and characterized by Gram staining, serotyping and susceptibility to penicillin. In this study....... The majority of isolates were penicillin intermediate resistant. In conclusion, two clones within serotype 19F were found to be dominating in pneumococcal carriage in Accra and Tamale in Ghana. Furthermore, it seems as though the clonal distribution of serotype 19F may be different from what is currently known...

  6. Transcriptomic variation in a coral reveals pathways of clonal organisation

    DEFF Research Database (Denmark)

    K Bay, Line; Nielsen, Henrik Bjørn; Jarmer, Hanne Østergaard


    A microarray study was undertaken to examine the potential for clonal gene expression variation in a branching reef building coral, Acropora millepora. The role of small-scale gradients in light and water flow was examined by comparing gene expression levels between branch elevation (tip and base......) and position (centre and edge) of replicate coral colonies (n=3). Analyses of variance revealed that almost 60% of variation in gene expression was present between colonies and 34 genes were considered differentially expressed between colonies (minimum P=6.5 x 10(-4)). These genes are associated with energy...... of corymbose-like branching coral colonies such as A. millepora. Four genes were differentially expressed between the tip and base of branches (P=3.239 x 10(-4)) and were associated with lysosome lipase activity and fluorescence, suggesting that branch tips may encounter higher pathogen loads or levels...

  7. Aging, Clonality, and Rejuvenation of Hematopoietic Stem Cells. (United States)

    Akunuru, Shailaja; Geiger, Hartmut


    Aging is associated with reduced organ function and increased disease incidence. Hematopoietic stem cell (HSC) aging driven by both cell intrinsic and extrinsic factors is linked to impaired HSC self-renewal and regeneration, aging-associated immune remodeling, and increased leukemia incidence. Compromised DNA damage responses and the increased production of reactive oxygen species (ROS) have been previously causatively attributed to HSC aging. However, recent paradigm-shifting concepts, such as global epigenetic and cytoskeletal polarity shifts, cellular senescence, as well as the clonal selection of HSCs upon aging, provide new insights into HSC aging mechanisms. Rejuvenating agents that can reprogram the epigenetic status of aged HSCs or senolytic drugs that selectively deplete senescent cells provide promising translational avenues for attenuating hematopoietic aging and, potentially, alleviating aging-associated immune remodeling and myeloid malignancies.

  8. Black locust (Robinia pseudoacacia L.) clonal seed orchards in Hungary

    Institute of Scientific and Technical Information of China (English)

    Károly Redei; Zoltán Osváth-Bujtás; Irina Veperdi


    Black locust (Robinia pseudoacacia L.) is one of the most important stand-forming tree species in Hungary and its importance is increasing in many countries. The main aim of the discussed new selection programme is to identify black locust clones with good performance and good form for setting up clonal seed orchards. As a result of selection programme 16 new black locust clones have been improved. In spring 2002 a black locust seed orchard was established with the newly selected clones. About 40% of the plants can be considered to belong to the height growth rate class 1 and 2. Hungary was the first country where micropropagated black locust planting material was used for seed orchard establishment.

  9. Clonal expansion of renal cell carcinoma-infiltrating T lymphocytes

    DEFF Research Database (Denmark)

    Sittig, Simone; Køllgaard, Tania; Grønbæk, Kirsten


    T lymphocytes can mediate the destruction of cancer cells by virtue of their ability to recognize tumor-derived antigenic peptides that are presented on the cell surface in complex with HLA molecules and expand. Thus, the presence of clonally expanded T cells within neoplastic lesions...... is an indication of ongoing HLA-restricted T cell-mediated immune responses. Multiple tumors, including renal cell carcinomas (RCCs), are often infiltrated by significant amounts of T cells, the so-called tumor-infiltrating lymphocytes (TILs). In the present study, we analyzed RCC lesions (n = 13) for the presence...... of expanded T-cell clonotypes using T-cell receptor clonotype mapping. Surprisingly, we found that RCCs comprise relatively low numbers of distinct expanded T-cell clonotypes as compared with melanoma lesions. The numbers of different T-cell clonotypes detected among RCC-infiltrating lymphocytes were...

  10. Concurrent interspecies and clonal dissemination of OXA-48 carbapenemase. (United States)

    Arana, D M; Saez, D; García-Hierro, P; Bautista, V; Fernández-Romero, S; Ángel de la Cal, M; Alós, J I; Oteo, J


    Several isolates of four different carbapenemase-producing Enterobacteriaceae species were recovered from a patient hospitalized for 4 months in a teaching hospital in Madrid. These species comprised seven Klebsiella pneumoniae belonging to ST15, four Escherichia coli belonging to ST2531, two Serratia marcescens and one Citrobacter freundii. This patient was the index case of a small outbreak of four patients infected and/or colonized by carbapenemase-producing K. pneumoniae. Molecular results identified the bla(OXA-48) gene in all Enterobacteriaceae isolates from the index case and in all isolates from the other three patients, suggesting intra- and interpatient dissemination. Our results highlight the great ability of OXA-48 carbapenemase to spread among different enterobacterial species by both clonal and nonclonal dissemination. Copyright © 2014 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

  11. Environmental gradients structure Daphnia pulex × pulicaria clonal distribution. (United States)

    Pantel, J H; Juenger, T E; Leibold, M A


    The rarity of eukaryotic asexual reproduction is frequently attributed to the disadvantage of reduced genetic variation relative to sexual reproduction. However, parthenogenetic lineages that evolved repeatedly from sexual ancestors can generate regional pools of phenotypically diverse clones. Various theories to explain the maintenance of this genetic diversity as a result of environmental and spatial heterogeneity [frozen niche variation (FNV), general-purpose genotype] are conceptually similar to community ecological explanations for the maintenance of regional species diversity. We employed multivariate statistics common in community ecological research to study population genetic structure in the freshwater crustacean, Daphnia pulex × pulicaria. This parthenogenetic hybrid arose repeatedly from sexual ancestors. Daphnia pulex × pulicaria populations harboured substantial genetic variation among populations and the clonal composition at each pond corresponded to nutrient levels and invertebrate predator densities. The interclonal selection process described by the FNV hypothesis likely structured our D. pulex × pulicaria populations.

  12. Immunostimulatory and anti-neoplasm effects of a novel palindrome CpG oligodeoxynucleotide in mice

    Institute of Scientific and Technical Information of China (English)

    Hai-yan DU; Zhong-ming TANG; Hai-feng SONG; Li-hou DONG; Bi-jun ZHAO; Jie FU; Qing-qing WANG; FangCHEN; Lun OU; Na LI; Xiao SUN


    Aim:DNAs containing unmethylated CpG motifs can stimulate innate and adaptive immunity.The aim of this study was to investigate the immunostimulatory and anti-neoplasm effects of a novel CpG oligodeoxynucleotide,ODN10,in tumor-bearing mice.Methods:B16 melanoma-bearing C57BL/6 mice were administered ip or sc with ODN10 or conventional CpG ODN1826 on the indicated days post inoculation.The animal survival rate and the inhibitory effect on tumor growth were observed in vivo.B and T lymphocyte proliferation,natural killing cell cytotoxicity and the phagocytic ability of peritoneal macrophages from the animals were determined using [3H]-thymidine incorporation assay,4-h 51Cr release assay and neutral red chromometry method,respectively.The serum levels of IL-12,IL-4,and IgE were quantified using ELISA assays.Histological examination of tumor tissues was performed after HE staining,and the expression of PCNA,CD63,and CD80 in tumor tissues was analyzed with immunohistochemistry.Results:ODN10 (1,5,and 25 mg/kg) significantly inhibited the growth and metastasis of the tumor,and significantly prolonged the survival of tumor-bearing mice,as compared with ODN1826,The immune status was suppressed in tumor-bearing mice.Both ODN10 and ODN1826 significantly reversed the suppressed immunoactivities in tumor-bearing mice,which included promoting B and T lymphocyte proliferation,enhancing NK cell and peritoneal macrophage activities,inducing IL-12 secretion and inhibiting IL-4 and IgE secretion.Further,CpG ODNs decreased PCNA and CD63 expression while induced expression of CD80.ODN10 presented more potent activity,and displayed the most prominent immunostimulatory potential.Conclusion:ODN10 produces prominent immunomodulatory effects on cellular immunity in tumor-bearing mice,which might help reverse the established Th2-type responses to the Th1-type responses,thus may be used as a potent anti-tumor immunotherapy agent or adjuvant.

  13. Microfabricated Arrays for Splitting and Assay of Clonal Colonies (United States)

    Gach, Philip C.; Xu, Wei; King, Samantha J.; Sims, Christopher E.; Bear, James; Allbritton, Nancy L.


    A microfabricated platform was developed for highly parallel and efficient colony picking, splitting and clone identification. A pallet array provided patterned cell colonies which mated to a second printing array composed of bridging microstructures formed by a supporting base and attached post. The posts enabled mammalian cells from colonies initially cultured on the pallet array to migrate to corresponding sites on the printing array. Separation of the arrays simultaneously split the colonies creating a patterned replica. Optimization of array elements provided transfer efficiencies greater than 90% using bridging posts of 30 μm diameter and 100 μm length and total colony numbers of 3000. Studies using five mammalian cell lines demonstrated that a variety of adherent cell types could be cultured and effectively split with printing efficiencies of 78–92%. To demonstrate the technique’s utility, clonal cell lines with siRNA knockdown of Coronin 1B were generated using the arrays and compared to a traditional FACS/Western Blotting-based approach. Identification of target clones required a destructive assay to identify cells with an absence of Coronin 1B brought about by the successful infection of interfering shRNA construct. By virtue of miniaturization and its parallel format, the platform enabled the identification and generation of 12 target clones from a starting sample of only 3900 cells and required only 5-man hours over 11 days. In contrast, the traditional method required 500,000 cells and generated only 5 target clones with 34-man hours expended over 47 days. These data support the considerable reduction in time, manpower and reagents using the miniaturized platform for clonal selection by destructive assay versus conventional approaches. PMID:23153031

  14. Negative plant soil feedback explaining ring formation in clonal plants. (United States)

    Cartenì, Fabrizio; Marasco, Addolorata; Bonanomi, Giuliano; Mazzoleni, Stefano; Rietkerk, Max; Giannino, Francesco


    Ring shaped patches of clonal plants have been reported in different environments, but the mechanisms underlying such pattern formation are still poorly explained. Water depletion in the inner tussocks zone has been proposed as a possible cause, although ring patterns have been also observed in ecosystems without limiting water conditions. In this work, a spatially explicit model is presented in order to investigate the role of negative plant-soil feedback as an additional explanation for ring formation. The model describes the dynamics of the plant biomass in the presence of toxicity produced by the decomposition of accumulated litter in the soil. Our model qualitatively reproduces the emergence of ring patterns of a single clonal plant species during colonisation of a bare substrate. The model admits two homogeneous stationary solutions representing bare soil and uniform vegetation cover which depend only on the ratio between the biomass death and growth rates. Moreover, differently from other plant spatial patterns models, but in agreement with real field observations of vegetation dynamics, we demonstrated that the pattern dynamics always lead to spatially homogeneous vegetation covers without creation of stable Turing patterns. Analytical results show that ring formation is a function of two main components, the plant specific susceptibility to toxic compounds released in the soil by the accumulated litter and the decay rate of these same compounds, depending on environmental conditions. These components act at the same time and their respective intensities can give rise to the different ring structures observed in nature, ranging from slight reductions of biomass in patch centres, to the appearance of marked rings with bare inner zones, as well as the occurrence of ephemeral waves of plant cover. Our results highlight the potential role of plant-soil negative feedback depending on decomposition processes for the development of transient vegetation patterns.

  15. Genome-Wide Locations of Potential Epimutations Associated with Environmentally Induced Epigenetic Transgenerational Inheritance of Disease Using a Sequential Machine Learning Prediction Approach.

    Directory of Open Access Journals (Sweden)

    M Muksitul Haque

    Full Text Available Environmentally induced epigenetic transgenerational inheritance of disease and phenotypic variation involves germline transmitted epimutations. The primary epimutations identified involve altered differential DNA methylation regions (DMRs. Different environmental toxicants have been shown to promote exposure (i.e., toxicant specific signatures of germline epimutations. Analysis of genomic features associated with these epimutations identified low-density CpG regions (<3 CpG / 100bp termed CpG deserts and a number of unique DNA sequence motifs. The rat genome was annotated for these and additional relevant features. The objective of the current study was to use a machine learning computational approach to predict all potential epimutations in the genome. A number of previously identified sperm epimutations were used as training sets. A novel machine learning approach using a sequential combination of Active Learning and Imbalance Class Learner analysis was developed. The transgenerational sperm epimutation analysis identified approximately 50K individual sites with a 1 kb mean size and 3,233 regions that had a minimum of three adjacent sites with a mean size of 3.5 kb. A select number of the most relevant genomic features were identified with the low density CpG deserts being a critical genomic feature of the features selected. A similar independent analysis with transgenerational somatic cell epimutation training sets identified a smaller number of 1,503 regions of genome-wide predicted sites and differences in genomic feature contributions. The predicted genome-wide germline (sperm epimutations were found to be distinct from the predicted somatic cell epimutations. Validation of the genome-wide germline predicted sites used two recently identified transgenerational sperm epimutation signature sets from the pesticides dichlorodiphenyltrichloroethane (DDT and methoxychlor (MXC exposure lineage F3 generation. Analysis of this positive validation

  16. Combinations of various CpG motifs cloned into plasmid backbone modulate and enhance protective immunity of viral replicon DNA anthrax vaccines. (United States)

    Yu, Yun-Zhou; Ma, Yao; Xu, Wen-Hui; Wang, Shuang; Sun, Zhi-Wei


    DNA vaccines are generally weak stimulators of the immune system. Fortunately, their efficacy can be improved using a viral replicon vector or by the addition of immunostimulatory CpG motifs, although the design of these engineered DNA vectors requires optimization. Our results clearly suggest that multiple copies of three types of CpG motifs or combinations of various types of CpG motifs cloned into a viral replicon vector backbone with strong immunostimulatory activities on human PBMC are efficient adjuvants for these DNA vaccines to modulate and enhance protective immunity against anthrax, although modifications with these different CpG forms in vivo elicited inconsistent immune response profiles. Modification with more copies of CpG motifs elicited more potent adjuvant effects leading to the generation of enhanced immunity, which indicated a CpG motif dose-dependent enhancement of antigen-specific immune responses. Notably, the enhanced and/or synchronous adjuvant effects were observed in modification with combinations of two different types of CpG motifs, which provides not only a contribution to the knowledge base on the adjuvant activities of CpG motifs combinations but also implications for the rational design of optimal DNA vaccines with combinations of CpG motifs as "built-in" adjuvants. We describe an efficient strategy to design and optimize DNA vaccines by the addition of combined immunostimulatory CpG motifs in a viral replicon DNA plasmid to produce strong immune responses, which indicates that the CpG-modified viral replicon DNA plasmid may be desirable for use as vector of DNA vaccines.

  17. Beyond the simplicity of Mendelian inheritance. (United States)

    Schacherer, Joseph


    Elucidating the underlying rules that govern the phenotypic diversity observed in natural populations is an old but still unaccomplished goal in biology. In 1865, Gregor Mendel paved the way for the dissection of the underlying genetic basis of traits by setting out to understand the principles of heredity. To date, we still lack a global overview of the spectrum and continuum existing between Mendelian and complex traits within any natural population. In this respect, we recently performed a species-wide survey of Mendelian traits across a large population of isolates using the yeast Saccharomyces cerevisiae. By analyzing the distribution and the inheritance patterns of the trait, we have clearly shown that monogenic mutations can display a significant, variable, and continuous expressivity across different genetic backgrounds. Our study also demonstrated that combining the elegancy of both classical genetics and high-throughput genomics is more than valuable to dissect the genotype-phenotype relationship in natural populations. Copyright © 2016 Académie des sciences. Published by Elsevier SAS. All rights reserved.

  18. Epigenetic inheritance and plasticity: The responsive germline. (United States)

    Jablonka, Eva


    Developmental plasticity, the capacity of a single genotype to give rise to different phenotypes, affects evolutionary dynamics by influencing the rate and direction of phenotypic change. It is based on regulatory changes in gene expression and gene products, which are partially controlled by epigenetic mechanisms. Plasticity involves not just epigenetic changes in somatic cells and tissues; it can also involve changes in germline cells. Germline epigenetic plasticity increases evolvability, the capacity to generate heritable, selectable, phenotypic variations, including variations that lead to novel functions. I discuss studies that show that some complex adaptive responses to new challenges are mediated by germline epigenetic processes, which can be transmitted over variable number of generations, and argue that the heritable variations that are generated epigenetically have an impact on both small-scale and large-scale aspects of evolution. First, I review some recent ecological studies and models that show that germline (gametic) epigenetic inheritance can lead to cumulative micro-evolutionary changes that are rapid and semi-directional. I suggest that "priming" and "epigenetic learning" may be of special importance in generating heritable, fine-tuned adaptive responses in populations. Second, I consider work showing how genomic and environmental stresses can also lead to epigenome repatterning, and produce changes that are saltational.

  19. Desmopressin in inherited disorders of platelet function. (United States)

    Coppola, A; Di Minno, G


    Following the first clinical use in haemophilia and von Willebrand disease in 1977, the synthetic analogue of vasopressin 1-deamino-8-D-arginine vasopressin (DDAVP, desmopressin) was successfully employed for the management of a series of bleeding disorders, including congenital and acquired defects of platelet function. In this setting, few haemostatic approaches are available and, in particular for severe bleeding and major invasive procedures, the transfusion of platelet concentrates is the first-choice treatment. Therefore, DDAVP was (and remains) an attractive therapeutic alternative, being well tolerated, cost-saving, administrable at home (by the intranasal or subcutaneous concentrated formulations) and, in particular, enabling the avoidance of blood product exposition and the related risks (allergic reactions, transfusion transmitted infections). Despite three decades of clinical use, cellular mechanisms of haemostatic effects of DDAVP in platelet defects remain poorly known and the excellent results reported in some case series have not been strengthened by rigorous clinical trials, hampered by the rarity and the heterogeneity of these disorders. However, clinical experience more than evidence-based medicine reserved an established place to DDAVP in the management of inherited platelet disorders. This review will focus the available clinical data and the open issues of DDAVP in this setting.

  20. Inheritance of seed coat color in sesame

    Directory of Open Access Journals (Sweden)

    Hernán Laurentin


    Full Text Available The objective of this work was to determine the inheritance mode of seed coat color in sesame. Two crosses and their reciprocals were performed: UCLA37 x UCV3 and UCLA90 x UCV3, of which UCLA37 and UCLA90 are white seed, and UCV3 is brown seed. Results of reciprocal crosses within each cross were identical: F1 seeds had the same phenotype as the maternal parent, and F2 resulted in the phenotype brown color. These results are consistent only with the model in which the maternal effect is the responsible for this trait. This model was validated by recording the seed coat color of 100 F2 plants (F3 seeds from each cross with its reciprocal, in which the 3:1 expected ratio for plants producing brown and white seeds was tested with the chi-square test. Sesame seed color is determined by the maternal genotype. Proposed names for the alleles participating in sesame seed coat color are: Sc1, for brown color; and Sc2, for white color; Sc1 is dominant over Sc2.

  1. Genetics of inherited primary arrhythmia disorders

    Directory of Open Access Journals (Sweden)

    Spears DA


    Full Text Available Danna A Spears, Michael H Gollob Division of Cardiology – Electrophysiology, University Health Network, Toronto General Hospital, Toronto, ON, Canada Abstract: A sudden unexplained death is felt to be due to a primary arrhythmic disorder when no structural heart disease is found on autopsy, and there is no preceding documentation of heart disease. In these cases, death is presumed to be secondary to a lethal and potentially heritable abnormality of cardiac ion channel function. These channelopathies include congenital long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, Brugada syndrome, and short QT syndrome. In certain cases, genetic testing may have an important role in supporting a diagnosis of a primary arrhythmia disorder, and can also provide prognostic information, but by far the greatest strength of genetic testing lies in the screening of family members, who may be at risk. The purpose of this review is to describe the basic genetic and molecular pathophysiology of the primary inherited arrhythmia disorders, and to outline a rational approach to genetic testing, management, and family screening. Keywords: long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, Brugada syndrome, short QT syndrome, genetics

  2. On the role of sensory feedbacks in rowat-selverston CpG to improve robot legged locomotion. (United States)

    Amrollah, Elmira; Henaff, Patrick


    This paper presents the use of Rowat and Selverston-type of central pattern generator (CPG) to control locomotion. It focuses on the role of afferent exteroceptive and proprioceptive signals in the dynamic phase synchronization in CPG legged robots. The sensori-motor neural network architecture is evaluated to control a two-joint planar robot leg that slips on a rail. Then, the closed loop between the CPG and the mechanical system allows to study the modulation of rhythmic patterns and the effect of the sensing loop via sensory neurons during the locomotion task. Firstly simulations show that the proposed architecture easily allows to modulate rhythmic patterns of the leg, and therefore the velocity of the robot. Secondly, simulations show that sensori-feedbacks from foot/ground contact of the leg make the hip velocity smoother and larger. The results show that the Rowat-Selverston-type CPG with sensory feedbacks is an effective choice for building adaptive neural CPGs for legged robots.

  3. Developmentally programmed 3' CpG island methylation confers tissue- and cell-type-specific transcriptional activation (United States)

    During development, a small but significant number of CpG islands (CGIs) becomes methylated. The timing of developmentally programmed CGI methylation and associated mechanisms of transcriptional regulation during cellular differentiation, however, remain poorly characterized. Here we used genome-wid...

  4. 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


    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}.

  5. Epigenetic inactivation of the CpG demethylase TET1 as a DNA methylation feedback loop in human cancers (United States)

    Li, Lili; Li, Chen; Mao, Haitao; Du, Zhenfang; Chan, Wai Yee; Murray, Paul; Luo, Bing; Chan, Anthony TC; Mok, Tony SK; Chan, Francis KL; Ambinder, Richard F; Tao, Qian


    Promoter CpG methylation is a fundamental regulatory process of gene expression. TET proteins are active CpG demethylases converting 5-methylcytosine to 5-hydroxymethylcytosine, with loss of 5 hmC as an epigenetic hallmark of cancers, indicating critical roles of TET proteins in epigenetic tumorigenesis. Through analysis of tumor methylomes, we discovered TET1 as a methylated target, and further confirmed its frequent downregulation/methylation in cell lines and primary tumors of multiple carcinomas and lymphomas, including nasopharyngeal, esophageal, gastric, colorectal, renal, breast and cervical carcinomas, as well as non-Hodgkin, Hodgkin and nasal natural killer/T-cell lymphomas, although all three TET family genes are ubiquitously expressed in normal tissues. Ectopic expression of TET1 catalytic domain suppressed colony formation and induced apoptosis of tumor cells of multiple tissue types, supporting its role as a broad bona fide tumor suppressor. Furthermore, TET1 catalytic domain possessed demethylase activity in cancer cells, being able to inhibit the CpG methylation of tumor suppressor gene (TSG) promoters and reactivate their expression, such as SLIT2, ZNF382 and HOXA9. As only infrequent mutations of TET1 have been reported, compared to TET2, epigenetic silencing therefore appears to be the dominant mechanism for TET1 inactivation in cancers, which also forms a feedback loop of CpG methylation during tumorigenesis. PMID:27225590

  6. IL-4 and IL-13 alter plasmacytoid dendritic cell responsiveness to CpG DNA and herpes simplex virus-1

    NARCIS (Netherlands)

    Tel, J.; Torensma, R.; Figdor, C.G.; Vries, I.J.M. de


    Human plasmacytoid dendritic cells (pDCs) are found in skin lesions in a wide variety of diseases. The role of the microenvironment in these lesions on the function of human pDCs remains elusive. We sought to determine the effect of T(h)2 cytokines on the ability of human pDCs to respond to CpG

  7. CpG hypomethylation in a large domain encompassing the embryonic beta-like globin genes in primitive erythrocytes. (United States)

    Hsu, Mei; Mabaera, Rodwell; Lowrey, Christopher H; Martin, David I K; Fiering, Steven


    There is little evidence addressing the role of CpG methylation in transcriptional control of genes that do not contain CpG islands. This is reflected in the ongoing debate about whether CpG methylation merely suppresses retroelements or if it also plays a role in developmental and tissue-specific gene regulation. The genes of the beta-globin locus are an important model of mammalian developmental gene regulation and do not contain CpG islands. We have analyzed the methylation status of regions in the murine beta-like globin locus in uncultured primitive and definitive erythroblasts and other cultured primary and transformed cell types. A large ( approximately 20-kb) domain is hypomethylated only in primitive erythroid cells; it extends from the region just past the locus control region to before beta-major and encompasses the embryonic genes Ey, beta h1, and beta h0. Even retrotransposons in this region are hypomethylated in primitive erythroid cells. The existence of this large developmentally regulated domain of hypomethylation supports a mechanistic role for DNA methylation in developmental regulation of globin genes.

  8. CpG Hypomethylation in a Large Domain Encompassing the Embryonic β-Like Globin Genes in Primitive Erythrocytes▿ † (United States)

    Hsu, Mei; Mabaera, Rodwell; Lowrey, Christopher H.; Martin, David I. K.; Fiering, Steven


    There is little evidence addressing the role of CpG methylation in transcriptional control of genes that do not contain CpG islands. This is reflected in the ongoing debate about whether CpG methylation merely suppresses retroelements or if it also plays a role in developmental and tissue-specific gene regulation. The genes of the β-globin locus are an important model of mammalian developmental gene regulation and do not contain CpG islands. We have analyzed the methylation status of regions in the murine β-like globin locus in uncultured primitive and definitive erythroblasts and other cultured primary and transformed cell types. A large (∼20-kb) domain is hypomethylated only in primitive erythroid cells; it extends from the region just past the locus control region to before β-major and encompasses the embryonic genes Ey, βh1, and βh0. Even retrotransposons in this region are hypomethylated in primitive erythroid cells. The existence of this large developmentally regulated domain of hypomethylation supports a mechanistic role for DNA methylation in developmental regulation of globin genes. PMID:17452448

  9. CpG island methylator phenotype and its relationship with prognosis in adult acute leukemia patients. (United States)

    Fu, Hai-Ying; Wu, Dan-Sen; Zhou, Hua-Rong; Shen, Jian-Zhen


    To investigated the relationship between CpG island methylator phenotype (CIMP) and prognosis in adults with acute leukemia. Bone marrow samples from 53 acute myeloid leukemia and 50 acute lymphoblastic leukemia patients were collected. The methylation status of 18 tumor suppressor genes was determined using methylation-specific polymerase chain reaction. Greater than 30% of acute leukemia patients had methylated p15, p16, CDH1, CDH13, RUNX3, sFRP1, ID4, and DLC-1 genes; methylation of ≥4 were defined as CIMP positive. Age, type of leukemia, white blood cell count, and CIMP status were significantly associated with recurrence-free survival (RFS) and overall survival (OS) (P acute leukemia.

  10. Regulation of a Mammalian Gene Bearing a CpG Island Promoter and a Distal Enhancer

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    Georgina Berrozpe


    Full Text Available A quantitative nucleosome occupancy assay revealed rules for nucleosome disposition in yeast and showed how disposition affects regulation of the GAL genes. Here, we show how those findings apply to the control of Kit, a mammalian gene. The Kit promoter lies in a CpG island, and its enhancer (active in mast cells lies some 150 kb upstream. Nucleosomes form with especially high avidities at the Kit promoter, a reaction that, we surmise, ensures extremely low basal expression. In mast cells, transcriptional activators displace nucleosomes that are less tightly formed at the Kit enhancer. In turn, the active enhancer replaces a single Kit promoter nucleosome with the transcriptional machinery, thereby inducing transcription over 1,000-fold. As at the yeast GAL genes, the inhibitory effects of nucleosomes facilitate high factors of induction by mammalian activators working in the absence of specific repressors.

  11. Aberrant promoter CpG methylation and its translational applications in breast cancer

    Institute of Scientific and Technical Information of China (English)

    Ting-Xiu Xiang; Ying Yuan; Li-Li Li; Zhao-Hui Wang; Liang-Ying Dan; Yan Chen; Guo-Sheng Ren; Qian Tao


    Breast cancer is a complex disease driven by multiple factors including both genetic and epigenetic alterations.Recent studies revealed that abnormal gene expression induced by epigenetic changes,including aberrant promoter methylation and histone modification,plays a critical role in human breast carcinogenesis.Silencing of tumor suppressor genes (TSGs) by promoter CpG methylation facilitates cells growth and survival advantages and further results in tumor initiation and progression,thus directly contributing to breast tumorigenesis.Usually,aberrant promoter methylation of TSGs,which can be reversed by pharmacological reagents,occurs at the early stage of tumorigenesis and therefore may serve as a potential tumor marker for early diagnosis and therapeutic targeting of breast cancer.In this review,we summarize the epigenetic changes of multiple TSGs involved in breast pathogenesis and their potential clinical applications as tumor markers for early detection and treatment of breast cancer.

  12. CPG-7909 (PF-3512676, ProMune): toll-like receptor-9 agonist in cancer therapy. (United States)

    Murad, Yanal M; Clay, Timothy M; Lyerly, H Kim; Morse, Michael A


    Stimulation of toll-like receptor (TLR)9 activates human plasmacytoid dendritic cells and B cells, and induces potent innate immune responses in preclinical tumor models and in patients. CpG oligodeoxynucleotides (ODNs) are TLR9 agonists that show promising results as vaccine adjuvants and in the treatment of cancers, infections, asthma and allergy. PF-3512676 (ProMune) was developed as a TLR9 agonist for the treatment of cancer as monotherapy and as an adjuvant in combination with chemo- and immunotherapy. Phase I and II trials have tested this drug in several hematopoietic and solid tumors. Pfizer has initiated Phase III trials to test PF-3512676 in combination with standard chemotherapy for non-small-cell lung cancer.

  13. Co-administration of a CpG adjuvant (VaxImmune, CPG 7909) with CETP vaccines increased immunogenicity in rabbits and mice. (United States)

    Thomas, Lawrence J; Hammond, Russell A; Forsberg, Eric M; Geoghegan-Barek, Kathleen M; Karalius, Brad H; Marsh, Henry C; Rittershaus, Charles W


    Cholesteryl ester transfer protein (CETP) is a plasma glycoprotein that facilitates the transfer of neutral lipids and phospholipids between lipoproteins and contributes to the regulation of the plasma concentration of high density lipoprotein cholesterol (HDL-C). Vaccines have been developed that elicit antibodies that bind to and reduce the lipid transfer function of CETP as a way to increase the plasma concentration of HDL-C and prevent or treat atherosclerosis. This study assessed the immunogenicity of two vaccine peptides. The first, CETi-1, is a dimerized synthetic peptide, including residues 461-476 of human CETP and residues 830-843 of tetanus toxoid, TT(830-843). The second, PADRE-CETP, is a monomeric peptide, in which a PADRE T cell epitope (aK-Cha-VAAWTLKAa) replaces the TT(830-843) T cell epitope of CETi-1. Both peptides were formulated with aluminum-containing adjuvants (Alhydrogel), and tested in mice and rabbits with or without the co-administration of the investigational TLR9 agonist VaxImmune (CPG 7909). In both mice and rabbits, the vaccine peptide utilizing the PADRE T cell epitope elicited stronger anti-CETP antibody responses than the CETi-1 vaccine. Also, co-administration of VaxImmune enhanced the anti-CETP antibody responses to both vaccines. Isotype analysis of the murine anti-CETP antibody response to both vaccines demonstrated a switch from IgG1 to IgG2a upon co-administration of VaxImmune. We conclude that (1) the PADRE T cell epitope is more potent than the TT(830-843) epitope in providing help for the anti-CETP antibody response; and (2) co-administration of VaxImmune with either vaccine increased immunogenicity as measured by antibody response.

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

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    James Crooks


    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.

  15. African 2, a Clonal Complex of Mycobacterium bovis Epidemiologically Important in East Africa▿ † (United States)

    Berg, Stefan; Garcia-Pelayo, M. Carmen; Müller, Borna; Hailu, Elena; Asiimwe, Benon; Kremer, Kristin; Dale, James; Boniotti, M. Beatrice; Rodriguez, Sabrina; Hilty, Markus; Rigouts, Leen; Firdessa, Rebuma; Machado, Adelina; Mucavele, Custodia; Ngandolo, Bongo Nare Richard; Bruchfeld, Judith; Boschiroli, Laura; Müller, Annélle; Sahraoui, Naima; Pacciarini, Maria; Cadmus, Simeon; Joloba, Moses; van Soolingen, Dick; Michel, Anita L.; Djønne, Berit; Aranaz, Alicia; Zinsstag, Jakob; van Helden, Paul; Portaels, Françoise; Kazwala, Rudovick; Källenius, Gunilla; Hewinson, R. Glyn; Aseffa, Abraham; Gordon, Stephen V.; Smith, Noel H.


    We have identified a clonal complex of Mycobacterium bovis isolated at high frequency from cattle in Uganda, Burundi, Tanzania, and Ethiopia. We have named this related group of M. bovis strains the African 2 (Af2) clonal complex of M. bovis. Af2 strains are defined by a specific chromosomal deletion (RDAf2) and can be identified by the absence of spacers 3 to 7 in their spoligotype patterns. Deletion analysis of M. bovis isolates from Algeria, Mali, Chad, Nigeria, Cameroon, South Africa, and Mozambique did not identify any strains of the Af2 clonal complex, suggesting that this clonal complex of M. bovis is localized in East Africa. The specific spoligotype pattern of the Af2 clonal complex was rarely identified among isolates from outside Africa, and the few isolates that were found and tested were intact at the RDAf2 locus. We conclude that the Af2 clonal complex is localized to cattle in East Africa. We found that strains of the Af2 clonal complex of M. bovis have, in general, four or more copies of the insertion sequence IS6110, in contrast to the majority of M. bovis strains isolated from cattle, which are thought to carry only one or a few copies. PMID:21097608

  16. The use of Hardy-Weinberg Equilibrium in clonal plant systems. (United States)

    Douhovnikoff, Vladimir; Leventhal, Matthew


    Traditionally population genetics precludes the use of the same genetic individual more than once in Hardy-Weinberg (HW) based calculations due to the model's explicit assumptions. However, when applied to clonal plant populations this can be difficult to do, and in some circumstances, it may be ecologically informative to use the ramet as the data unit. In fact, ecologists have varied the definition of the individual from a strict adherence to a single data point per genotype to a more inclusive approach of one data point per ramet. With the advent of molecular tools, the list of facultatively clonal plants and the recognition of their ecological relevance grows. There is an important risk of misinterpretation when HW calculations are applied to a clonal plant not recognized as clonal, as well as when the definition of the individual for those calculations is not clearly stated in a known clonal species. Focusing on heterozygosity values, we investigate cases that demonstrate the extreme range of potential modeling outcomes and describe the different contexts where a particular definition could better meet ecological modeling goals. We emphasize that the HW model can be ecologically relevant when applied to clonal plants, but caution is necessary in how it is used, reported, and interpreted. We propose that in known clonal plants, both genotype (GHet) and ramet (RHet) based calculations are reported to define the full range of potential values and better facilitate cross-study comparisons.

  17. Strong but diverging clonality - climate relationships of different plant clades explain weak overall pattern across China (United States)

    Ye, Duo; Liu, Guofang; Song, Yao-Bin; Cornwell, William K.; Dong, Ming; Cornelissen, Johannes H. C.


    The clonal strategy should be relatively important in stressful environments (i.e. of low resource availability or harsh climate), e.g. in cold habitats. However, our understanding of the distribution pattern of clonality along environmental gradients is still far from universal. The weakness and inconsistency of overall clonality-climate relationships across taxa, as reported in previous studies, may be due to different phylogenetic lineages having fundamental differences in functional traits other than clonality determining their climate response. Thus, in this study we compared the clonality-climate relationships along a latitudinal gradient within and between different lineages at several taxonomic levels, including four major angiosperm lineages (Magnoliidae, Monocotyledoneae, Superrosidae and Superasteridae), orders and families. To this aim we used a species clonality dataset for 4015 vascular plant species in 545 terrestrial communities across China. Our results revealed clear predictive patterns of clonality proportion in relation to environmental gradients for the predominant representatives of each of the taxonomic levels above, but the relationships differed in shape and strength between the 4 major angiosperm lineages, between the 12 orders and between the 12 families. These different relationships canceled out one another when all lineages at a certain taxonomic level were pooled. Our findings highlight the importance of explicitly accounting for the functional or taxonomic scale for studying variation in plant ecological strategy across environmental gradients.

  18. Hypereosinophilic Syndrome and Clonal Eosinophilia: Point-of-Care Diagnostic Algorithm and Treatment Update (United States)

    Tefferi, Ayalew; Gotlib, Jason; Pardanani, Animesh


    Acquired eosinophilia is operationally categorized into secondary, clonal, and idiopathic types. Causes of secondary eosinophilia include parasite infections, allergic or vasculitis conditions, drugs, and lymphoma. Clonal eosinophilia is distinguished from idiopathic eosinophilia by the presence of histologic, cytogenetic, or molecular evidence of an underlying myeloid malignancy. The World Health Organization classification system for hematologic malignancies recognizes 2 distinct subcategories of clonal eosinophilia: chronic eosinophilic leukemia, not otherwise specified and myeloid/lymphoid neoplasms with eosinophilia and mutations involving platelet-derived growth factor receptor α/β or fibroblast growth factor receptor 1. Clonal eosinophilia might also accompany other World Health Organization—defined myeloid malignancies, including chronic myelogenous leukemia, myelodysplastic syndromes, chronic myelomonocytic leukemia, and systemic mastocytosis. Hypereosinophilic syndrome, a subcategory of idiopathic eosinophilia, is defined by the presence of a peripheral blood eosinophil count of 1.5 × 109/L or greater for at least 6 months (a shorter duration is acceptable in the presence of symptoms that require eosinophil-lowering therapy), exclusion of both secondary and clonal eosinophilia, evidence of organ involvement, and absence of phenotypically abnormal and/or clonal T lymphocytes. The presence of the latter defines lymphocytic variant hyper eosinophilia, which is best classified under secondary eosinophilia. In the current review, we provide a simplified algorithm for distinguishing the various causes of clonal and idiopathic eosinophilia and discuss current therapy, including new drugs (imatinib mesylate, alemtuzumab, and mepolizumab). PMID:20053713

  19. African 2, a clonal complex of Mycobacterium bovis epidemiologically important in East Africa. (United States)

    Berg, Stefan; Garcia-Pelayo, M Carmen; Müller, Borna; Hailu, Elena; Asiimwe, Benon; Kremer, Kristin; Dale, James; Boniotti, M Beatrice; Rodriguez, Sabrina; Hilty, Markus; Rigouts, Leen; Firdessa, Rebuma; Machado, Adelina; Mucavele, Custodia; Ngandolo, Bongo Nare Richard; Bruchfeld, Judith; Boschiroli, Laura; Müller, Annélle; Sahraoui, Naima; Pacciarini, Maria; Cadmus, Simeon; Joloba, Moses; van Soolingen, Dick; Michel, Anita L; Djønne, Berit; Aranaz, Alicia; Zinsstag, Jakob; van Helden, Paul; Portaels, Françoise; Kazwala, Rudovick; Källenius, Gunilla; Hewinson, R Glyn; Aseffa, Abraham; Gordon, Stephen V; Smith, Noel H


    We have identified a clonal complex of Mycobacterium bovis isolated at high frequency from cattle in Uganda, Burundi, Tanzania, and Ethiopia. We have named this related group of M. bovis strains the African 2 (Af2) clonal complex of M. bovis. Af2 strains are defined by a specific chromosomal deletion (RDAf2) and can be identified by the absence of spacers 3 to 7 in their spoligotype patterns. Deletion analysis of M. bovis isolates from Algeria, Mali, Chad, Nigeria, Cameroon, South Africa, and Mozambique did not identify any strains of the Af2 clonal complex, suggesting that this clonal complex of M. bovis is localized in East Africa. The specific spoligotype pattern of the Af2 clonal complex was rarely identified among isolates from outside Africa, and the few isolates that were found and tested were intact at the RDAf2 locus. We conclude that the Af2 clonal complex is localized to cattle in East Africa. We found that strains of the Af2 clonal complex of M. bovis have, in general, four or more copies of the insertion sequence IS6110, in contrast to the majority of M. bovis strains isolated from cattle, which are thought to carry only one or a few copies.

  20. Fitness analysis of seed and vegetative reproduction of clonal tree Symplocos laurina

    Institute of Scientific and Technical Information of China (English)

    Zhang Yunchun; Du Xiaojun; Zhang Qiaoying; Gao Xianming; Su Zhixian


    There are two ways for Symplocos laurina to propagate: clonal reproduction and sexual reproduction.S.laurina adopted different ways to propagate and occupy space in different environments: under conditions with abundant water,nutrient resources,and lower light such as in an evergreen broad-leaved or a bamboo forest;survival rates and the ability of both clonal and sexual seedlings to occupy space,were relatively high.But clonal ramets took advantage both in terms of number and space.Therefore,clonal propagation predominated in such an environment.However,in habitats lacking sufficient nutrition and with higher light intensity,survival rates and space-occupying ability of two kinds of seedlings (sexual and asexual produced) were low and the space would be preempted by grown-up plantlets.A bottleneck in sexual "propagation appeared at the stage from seed to seedling,while in clonal propagation it appeared during the period from an asexual plantlet to a ramet.The way S.laurina invaded space was like that of a plantlet settled in a place and then occupied the space rapidly by clonal growth under conditions of abundant water and nutrient resources and lower light such as in an evergreen broad-leaved forest or a bamboo forest.Clonal seedlings showed a great advantage in the initial stages,but this advantage disappeared after 15 years.

  1. Identification of Triploid Individuals and Clonal Lines in Carassius Auratus Complex Using Microsatellites

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    Zhiyi Bai, Feng Liu, Jiale Li, Gen Hua Yue


    Full Text Available The Carassius auratus complex in natural populations includes diploid triploid and polyploidy individuals. Diploid individuals belong to the species Carassius auratus whereas triploid and polyploidy individuals are from the subspecies Carassius auratus gibelio. Triploid individuals are all female and reproduce clonally by gynogenesis. Therefore the Carassius auratus complex is an ideal system for studying evolution of unisexual reproduction. Identification of triploid individuals and clonal lines is the first step towards understanding of the evolution of unisexual clonal lines. We examined the ability of 10 microsatellites in identifying triploid individuals in 94 individuals from Japan and China. In 40 confirmed triploid individuals and eight confirmed diploid individuals, all triploid and diploid individuals can be identified by genotyping 10 microsatellite, and four triploid clonal lines were identified. Using the 10 microsatellites we genotyped 46 adult individuals (40 females and six males from a natural population in China and found that all six males were diploid whereas the majority of females (36 of 40 were triploid and three triploid clonal lines were detected. In 18 diploid individuals from China, all individuals showed different genotypes, suggesting there is no diploid clonal line in diploid crucian carp. A phylogenetic analysis of 94 individuals from China and Japan showed that triploid individuals and clonal lines have originated recurrently.

  2. The mode of inheritance in tetraploid cut roses. (United States)

    Koning-Boucoiran, C F S; Gitonga, V W; Yan, Z; Dolstra, O; van der Linden, C G; van der Schoot, J; Uenk, G E; Verlinden, K; Smulders, M J M; Krens, F A; Maliepaard, C


    Tetraploid hybrid tea roses (Rosa hybrida) represent most of the commercial cultivars of cut roses and form the basis for breeding programmes. Due to intensive interspecific hybridizations, modern cut roses are complex tetraploids for which the mode of inheritance is not exactly known. The segregation patterns of molecular markers in a tetraploid mapping population of 184 genotypes, an F(1) progeny from a cross of two heterozygous parents, were investigated for disomic and tetrasomic inheritance. The possible occurrence of double reduction was studied as well. We can exclude disomic inheritance, but while our observations are more in line with a tetrasomic inheritance, we cannot exclude that there is a mixture of both inheritance modes. Two novel parental tetraploid linkage maps were constructed using markers known from literature, combined with newly generated markers. Comparison with the integrated consensus diploid map (ICM) of Spiller et al. (Theor Appl Genet 122:489-500, 2010) allowed assigning numbers to each of the linkage groups of both maps and including small linkage groups. So far, the possibility of using marker-assisted selection in breeding of tetraploid cut roses and of other species with a tetrasomic or partly tetrasomic inheritance, is still limited due to the difficulties in establishing marker-trait associations. We used these tetraploid linkage maps to determine associations between markers, two morphological traits and powdery mildew resistance. The knowledge on inheritance and marker-trait associations in tetraploid cut roses will be of direct use to cut rose breeding.

  3. Maternal inheritance of chloroplast genome and paternal inheritance of mitochondrial genome in bananas (Musa acuminata). (United States)

    Fauré, S; Noyer, J L; Carreel, F; Horry, J P; Bakry, F; Lanaud, C


    Restriction fragment length polymorphisms (RFLPs) were used as markers to determine the transmission of cytoplasmic DNA in diploid banana crosses. Progenies from two controlled crosses were studied with heterologous cytoplasmic probes. This analysis provided evidence for a strong bias towards maternal transmission of chloroplast DNA and paternal transmission of mitochondrial DNA in Musa acuminata. These results suggest the existence of two separate mechanisms of organelle transmission and selection, but no model to explain this can be proposed at the present time. Knowledge of the organelle mode of inheritance constitutes an important point for phylogeny analyses in bananas and may offer a powerful tool to confirm hybrid origins.

  4. All and only CpG containing sequences are enriched in promoters abundantly bound by RNA polymerase II in multiple tissues

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    Myakishev Maxim V


    Full Text Available Abstract Background The promoters of housekeeping genes are well-bound by RNA polymerase II (RNAP in different tissues. Although the promoters of these genes are known to contain CpG islands, the specific DNA sequences that are associated with high RNAP binding to housekeeping promoters has not been described. Results ChIP-chip experiments from three mouse tissues, liver, heart ventricles, and primary keratinocytes, indicate that 94% of promoters have similar RNAP binding, ranging from well-bound to poorly-bound in all tissues. Using all 8-base pair long sequences as a test set, we have identified the DNA sequences that are enriched in promoters of housekeeping genes, focusing on those DNA sequences which are preferentially localized in the proximal promoter. We observe a bimodal distribution. Virtually all sequences enriched in promoters with high RNAP binding values contain a CpG dinucleotide. These results suggest that only transcription factor binding sites (TFBS that contain the CpG dinucleotide are involved in RNAP binding to housekeeping promoters while TFBS that do not contain a CpG are involved in regulated promoter activity. Abundant 8-mers that are preferentially localized in the proximal promoters and exhibit the best enrichment in RNAP bound promoters are all variants of six known CpG-containing TFBS: ETS, NRF-1, BoxA, SP1, CRE, and E-Box. The frequency of these six DNA motifs can predict housekeeping promoters as accurately as the presence of a CpG island, suggesting that they are the structural elements critical for CpG island function. Experimental EMSA results demonstrate that methylation of the CpG in the ETS, NRF-1, and SP1 motifs prevent DNA binding in nuclear extracts in both keratinocytes and liver. Conclusion In general, TFBS that do not contain a CpG are involved in regulated gene expression while TFBS that contain a CpG are involved in constitutive gene expression with some CpG containing sequences also involved in

  5. Inheritance after Apocalypse: the Dystopian Environment

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    Serban Dan Blidariu


    Full Text Available Utopias are perfect places but the term itself says that they are nowhere to be found, making them practically impossible. Dystopias, even if they are written as a warning of how things can get worse, seem much more probable. All utopian societies are systems of plenty where everyone has enough and no one lacks the basic necessities. Yet resources do not come out of nowhere. A political system may be needed in a utopia but it is not the sole condition. A barren environment would make perfection impossible. A devastated land, then, can lead to a dystopia. Our way of life is connected to the environment around us. A drastic change there would alter human behavior significantly. If utopia is the dream situation, the dystopia is obviously the nightmare. The late 20th century had a feeling of “the end”, a lot of finalities were imagined, including “the end of history”. However, once those notions were left behind, even dystopias started to imagine events happening in a post-apocalyptic situation. One such dystopia is The Road, a novel about the struggles of a father and a son trying to survive after an unnamed cataclysm. The father’s desire to take his child toward the sea, where he thinks it might be safe, also implies a journey through the devastated land. In their travel they will witness the devastation of nature and the changes that brings to human behavior, a change that was unwanted and, for the son, an inheritance the father was unwilling to pass on.

  6. Gene therapy for inherited retinal degenerations. (United States)

    Dalkara, Deniz; Sahel, José-Alain


    Gene therapy is quickly becoming a reality applicable in the clinic for inherited retinal diseases. Progress over the past decade has moved proof-of-concept gene therapies from bench to bedside. The remarkable success in safety and efficacy, in the phase I/II clinical trials for the form of the severe childhood-onset blindness, Leber's Congenital Amaurosis (LCA) type II (due to mutations in the RPE65 gene) generated significant interest and opened up possibilities for a new era of retinal gene therapies. Success in these clinical trials was due to combining the favorable features of both the retina as a target organ and adeno-associated virus (AAV) as a vector. The retina offers several advantages for gene therapy approaches. It is an anatomically defined structure that is readily accessible for therapy and has some degree of immune privilege, making it suitable for application of viral vectors. AAV, on the other hand, is a non-pathogenic helper dependent virus that has little immunogenicity. This viral vector transduces quiescent cells efficiently and thanks to its small size diffuses well in the interneural matrix, making it suitable for applications in neural tissue. Building on this initial clinical success with LCA II, we have now many opportunities to extend this proof-of-concept to other retinal diseases. This article will discuss what are some of the most imminent targets for such therapies and what are the challenges that we face in moving these therapies to the clinic. Copyright © 2014 Académie des sciences. Published by Elsevier SAS. All rights reserved.

  7. Dynamic recurrent Elman neural network based on immune clonal selection algorithm (United States)

    Wang, Limin; Han, Xuming; Li, Ming; Sun, Haibo; Li, Qingzhao


    Owing to the immune clonal selection algorithm introduced into dynamic threshold strategy has better advantage on optimizing multi-parameters, therefore a novel approach that the immune clonal selection algorithm introduced into dynamic threshold strategy, is used to optimize the dynamic recursion Elman neural network is proposed in the paper. The concrete structure of the recursion neural network, the connect weight and the initial values of the contact units etc. are done by evolving training and learning automatically. Thus it could realize to construct and design for dynamic recursion Elman neural networks. It could provide a new effective approach for immune clonal selection algorithm optimizing dynamic recursion neural networks.

  8. Electrophysiologic features of inherited demyelinating neuropathies: a reappraisal. (United States)

    Lewis, R A; Sumner, A J


    The observation that inherited demyelinating neuropathies tend to have uniform conduction slowing and acquired disorders (CIDP and variants) have nonuniform or multifocal slowing was made before the identification of genetic defects of specific myelin constituents that cause the different forms of Charcot-Marie-Tooth and other inherited disorders involving peripheral nerve myelin. It is becoming clear that the electrophysiologic aspects of these disorders are more complex than previously realized. We review the current information available on the electrophysiologic features of the inherited demyelinating neuropathies in hopes of clarifying the clinical electrodiagnostic features of these disorders as well as to shed light on the physiologic consequences of the different genetic mutations.

  9. Darwin and inheritance: the influence of Prosper Lucas. (United States)

    Noguera-Solano, Ricardo; Ruiz-Gutiérrez, Rosaura


    An important historical relation that has hardly been addressed is the influence of Prosper Lucas's Treatise on Natural Inheritance on the development of Charles Darwin's concepts related to inheritance. In this article we trace this historical connection. Darwin read Lucas's Treatise in 1856. His reading coincided with many changes concerning his prior ideas on the transmission and expression of characters. We consider that this reading led him to propose a group of principles regarding prepotency, hereditary diseases, morbid tendencies and atavism; following Lucas, he called these principles: laws of inheritance.

  10. Maternal inheritance of mitochondrial genomes and complex inheritance of chloroplast genomes in Actinidia Lind.: evidences from interspecific crosses. (United States)

    Li, Dawei; Qi, Xiaoqiong; Li, Xinwei; Li, Li; Zhong, Caihong; Huang, Hongwen


    The inheritance pattern of chloroplast and mitochondria is a critical determinant in studying plant phylogenetics, biogeography and hybridization. To better understand chloroplast and mitochondrial inheritance patterns in Actinidia (traditionally called kiwifruit), we performed 11 artificial interspecific crosses and studied the ploidy levels, morphology, and sequence polymorphisms of chloroplast DNA (cpDNA) and mitochondrial DNA (mtDNA) of parents and progenies. Sequence analysis showed that the mtDNA haplotypes of F1 hybrids entirely matched those of the female parents, indicating strictly maternal inheritance of Actinidia mtDNA. However, the cpDNA haplotypes of F1 hybrids, which were predominantly derived from the male parent (9 crosses), could also originate from the mother (1 cross) or both parents (1 cross), demonstrating paternal, maternal, and biparental inheritance of Actinidia cpDNA. The inheritance patterns of the cpDNA in Actinidia hybrids differed according to the species and genotypes chosen to be the parents, rather than the ploidy levels of the parent selected. The multiple inheritance modes of Actinidia cpDNA contradicted the strictly paternal inheritance patterns observed in previous studies, and provided new insights into the use of cpDNA markers in studies of phylogenetics, biogeography and introgression in Actinidia and other angiosperms.

  11. The protection of CpG ODNs and Yarrowia lipolytica harboring VP28 for shrimp Litopenaeus vannamei against White spot syndrome virus infection

    Directory of Open Access Journals (Sweden)

    Q Yi


    Full Text Available The white spot syndrome is one of the most serious disease which has caused high mortalities and huge economic losses to shrimp culture. In the present study, the oral administrations with CpG ODNs and Yarrowia lipolytica harboring VP28 (rVP28-yl as dietary supplement for shrimp Litopenaeus vannamei were conducted to evaluate their protective effects against WSSV. After feeding for 15 days, the cumulative mortality and the copy number of WSSV in CpG and rVP28-yl feeding shrimps were significantly lower when they were challenged by WSSV, compared with those in control shrimps (p < 0.05. The caspase-3 activity was suppressed in rVP28-yl feeding shrimps but ascended in CpG feeding shrimps after WSSV challenge. Besides, the PO activity in CpG feeding shrimps was significantly increased after feeding trial, and kept increasing post WSSV challenge (p < 0.05. While the increased NO production was observed both in CpG and rVP28-yl feeding shrimps after feeding trial and WSSV challenge. In addition, increased mRNA expression levels of STAT and Dicer were observed in CpG group post WSSV challenge. These results together indicated that oral feeding of CpG ODNs and rVP28-yl could enhance the innate non-specific immune responses especially antiviral immunity of shrimps in varying degrees, and increase their resistance against WSSV infection

  12. TGF-β1 inhibits the production of IFN in response to CpG DNA via ubiquitination of TNF receptor-associated factor (TRAF) 6. (United States)

    Naiki, Yoshikazu; Komatsu, Takayuki; Koide, Naoki; Dagvadorj, Jargalsaikhan; Yoshida, Tomoaki; Arditi, Moshe; Yokochi, Takashi


    The effect of TGF-β1 on CpG DNA-induced type I IFN production was examined by reconstituting a series of signaling molecules in TLR 3 signaling. TGF-β1 inhibited CpG DNA-induced IFN-α4 productivity in HeLa cells. Transfection of IFN regulatory factor (IRF)7 but not TNF receptor-associated factor (TRAF)6 and TRAF3 into cells triggered IFN-α4 productivity, and TGF-β1 inhibited IRF7-mediated type I IFN production in the presence of TRAF6. TGF-β1 induced ubiquitination of TRAF6, although CpG DNA did not induce it. Moreover, TGF-β1 accelerated the ubiquitination of TRAF6 in the presence of CpG DNA. TGF-β1 ubiquitinated TRAF6 at K63 but not K48. TGF-β1 also induced ubiquitination of IRF7. Further, TGF-β1 did not impair the interaction of IRF7 and TRAF6. CpG DNA induced the phosphorylation of IRF7 in the presence of TRAF6, whereas TGF-β1 inhibited the IRF7 phosphorylation. Blocking of TRAF6 ubiquitination abolished the inhibition of CpG DNA-induced type I IFN production by TGF-β. Taken together, TGF-β was suggested to inhibit CpG DNA-induced type I IFN production transcriptionally via ubiquitination of TRAF6.

  13. B-cell activating CpG ODN 1668 enhance the immune response of Pacific red snapper (Lutjanus peru) exposed to Vibrio parahaemolitycus. (United States)

    Cárdenas-Reyna, Tomás; Angulo, Carlos; Hori-Oshima, Sawako; Velázquez-Lizárraga, Esteban; Reyes-Becerril, Martha


    B-class CpG ODN 1668 is known to possess clear immunostimulatory properties. In this study, we investigated the potential ability of CpG ODN 1668 to enhance the immune response of Pacific red snapper exposed to Vibrio parahaemolyticus. Four different treatments were evaluated in Pacific red snapper: (1) stimulatory CpG ODN 1668, (2) stimulatory CpG ODN 1668 and V. parahaemolyticus, (3) exposure only to V. parahaemolyticus and (4) PBS. Samples were taken at 24, 72, 168 and 240 h of stimulation/infection. The results show that intraperitoneal injection of CpG-ODN 1668 enhanced the anti-protease, superoxide dismutase and catalase activities in serum. CpG ODN 1668 upregulated TLR9 and IgM gene expression in head-kidney, intestine and skin, with higher expression in head-kidney. A higher correlation was observed between TLR9 and IgM in head-kidney and intestine. Finally, no histopathological damages were observed in fish stimulated with CpG ODN 1668. In contrast, melanomacrophages-like structures were present in higher numbers in infected fish. Taken together, these results indicate that CpG ODN 1668 activates innate immune response and upregulate the TLR9 and IgM-mediated immune response. These results may be exploited for the control of Vibriosis in farmed Pacific red snapper.

  14. Hypermethylation of CpG island loci and hypomethylation of LINE-1 and Alu repeats in prostate adenocarcinoma and their relationship to clinicopathological features. (United States)

    Cho, N-Y; Kim, B-H; Choi, M; Yoo, E J; Moon, K C; Cho, Y-M; Kim, D; Kang, G H


    Promoter CpG island hypermethylation is an important carcinogenic event in prostate adenocarcinoma. Regardless of tissue type, human cancers have in common both focal CpG island hypermethylation and global genomic hypomethylation. The present study evaluated CpG island loci hypermethylation and LINE-1 and Alu repeat hypomethylation in prostate adenocarcinoma, analysed the relationship between them, and correlated these findings with clinicopathological features. We examined 179 cases of prostate adenocarcinoma and 30 cases of benign prostate hypertrophy for the methylation status of 22 CpG island loci and the methylation levels of LINE-1 and Alu repeats using methylation-specific polymerase chain reaction and combined bisulphite restriction analysis, respectively. The following 16 CpG island loci were found to display cancer-related hypermethylation: RASSF1A, GSTP1, RARB, TNFRSF10C, APC, BCL2, MDR1, ASC, TIG1, RBP1, COX2, THBS1, TNFRSF10D, CD44, p16, and RUNX3. Except for the last four CpG island loci, hypermethylation of each of the remaining 12 CpG island loci displayed a close association with one or more of the prognostic parameters (ie preoperative serum prostate specific antigen level, Gleason score sum, and clinical stage). Prostate adenocarcinoma with hypermethylation of each of ASC, COX2, RARB, TNFRSF10C, MDR1, TIG1, RBP1, NEUROG1, RASSF1A, and GSTP1 showed a significantly lower methylation level of Alu or LINE-1 than prostate adenocarcinoma without hypermethylation. In addition, hypomethylation of Alu or LINE-1 was closely associated with one or more of the above prognostic parameters. These data suggest that in tumour progression a close relationship exists between CpG island hypermethylation and the hypomethylation of repetitive elements, and that CpG island hypermethylation and DNA hypomethylation contribute to cancer progression.

  15. CPG 7909, an immunostimulatory TLR9 agonist oligodeoxynucleotide, as adjuvant to Engerix-B HBV vaccine in healthy adults: a double-blind phase I/II study. (United States)

    Cooper, C L; Davis, H L; Morris, M L; Efler, S M; Adhami, M Al; Krieg, A M; Cameron, D W; Heathcote, J


    Oligodeoxynucleotides containing immunostimulatory CpG motifs (CpG ODN) act as potent Th1-like immune enhancers with many antigens in animal models. We have extended these observations to the first clinical evaluation of the safety, tolerability and immunogenicity of CPG 7909 when added to a commercial HBV vaccine. In a randomized, double-blind phase I dose escalation study, healthy volunteers aged 18-35 years were vaccinated at 0, 4 and 24 weeks by intramuscular injection with Engerix-B (GlaxoSmithKline). The regular adult dose of 20 microg recombinant hepatitis B surface antigen (HBsAg) adsorbed to alum was administered mixed with saline (control) or with CPG 7909 at one of three doses (0.125, 0.5 or 1.0 mg). HBsAg-specific antibody responses (anti-HBs) appeared significantly sooner and were significantly higher at all timepoints up to and including 24 weeks in CPG 7909 recipients compared to control subjects (pCpG 7909-vaccinated subjects developed protective levels of anti-HBs IgG within just two weeks of the priming vaccine dose. A trend towards higher rates of positive cytotoxic T cell lymphocyte responses was noted in the two higher dose groups of CPG 7909 compared to controls. The most frequently reported adverse events were injection site reactions, flu-like symptoms and headache. While these were more frequent in CPG 7909 groups than in the control group (pCPG 7909 as an adjuvant to Engerix-B was well-tolerated and enhanced vaccine immunogenicity. CPG 7909 may allow the development of a two-dose prophylactic HBV vaccine.

  16. DNA analysis in inherited cardiomyopathies : Current status and clinical relevance

    NARCIS (Netherlands)

    Van Spaendonck-Zwarts, Karin Y.; Van den Berg, Maarten P.; Van Tintelen, J. Peter


    Most hypertrophic cardiomyopathies and a subset of dilated and arrhythmogenic right ventricular cardiomyopathies are familial diseases. They generally show an autosomal dominant pattern of inheritance and have underlying mutations in genes encoding sarcomeric, cytoskeletal, nuclear envelope, and des

  17. Interdisciplinary psychosocial care for families with inherited cardiovascular diseases. (United States)

    Caleshu, Colleen; Kasparian, Nadine A; Edwards, Katharine S; Yeates, Laura; Semsarian, Christopher; Perez, Marco; Ashley, Euan; Turner, Christian J; Knowles, Joshua W; Ingles, Jodie


    Inherited cardiovascular diseases pose unique and complex psychosocial challenges for families, including coming to terms with life-long cardiac disease, risk of sudden death, grief related to the sudden death of a loved one, activity restrictions, and inheritance risk to other family members. Psychosocial factors impact not only mental health but also physical health and cooperation with clinical recommendations. We describe an interdisciplinary approach to the care of families with inherited cardiovascular disease, in which psychological care provided by specialized cardiac genetic counselors, nurses, and psychologists is embedded within the cardiovascular care team. We report illustrative cases and the supporting literature to demonstrate common scenarios, as well as practical guidance for clinicians working in the inherited cardiovascular disease setting. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Paternal inheritance of mitochondrial DNA in the sheep (Ovine aries)

    National Research Council Canada - National Science Library

    Zhao, Xingbo; Chu, Mingxing; Li, Ning; Wu, Changxin


    Paternal inheritance of mitochondria DNA in sheep was discovered by examination of 152 sheep from 38 hybrid families for mtDNA D-loop polymorphisms using PCR-RFLP, amplification of repeated sequence...

  19. Environmentally Induced Epigenetic Transgenerational Inheritance of Reproductive Disease. (United States)

    Nilsson, Eric E; Skinner, Michael K


    Reproductive disease and fertility issues have dramatically increased in the human population over the last several decades, suggesting environmental impacts. Epigenetics provides a mechanistic link by which an organism can respond to environmental factors. Interestingly, environmentally induced epigenetic alterations in the germ line can promote aberrant gene expression and disease generationally. Environmentally induced epigenetic transgenerational inheritance is defined as germ-line transmission of altered epigenetic information between generations in the absence of continued environmental exposures. This form of nongenetic inheritance has been shown to directly influence fertility and reproductive disease. This review describes the studies in a variety of species that impact reproductive disease and abnormalities. Observations suggest serious attention be paid to the possibility that ancestral exposures to environmental insults promotes transgenerational inheritance of reproductive disease susceptibility. Environmentally induced epigenetic transgenerational inheritance appears to be an important contributing factor to reproductive disease in many organisms, including humans.

  20. Phenotypic inheritance induced by hairpin RNA in Drosophila

    Institute of Scientific and Technical Information of China (English)

    Huaguang Li; Yi Lu


    Phenotypic inheritance induced by RNA has been docu-mented in mouse and Caenorhabditis elegans. Here we report a similar inheritance in Drosophila. Mutant phe-notypes of eye defects and antenna duplication gener-ated from the crossing of one RNA interference (RNAi)transgenic line harboring one hairpin RNA transgene with a GAL4 driver line were inherited independently of the GAL4 driver. Hairpin RNA injection exper-iments demonstrated that the hairpin RNA could induce heritable mutant-like phenotypes on the eye and antenna. The penetrance of mutant phenotypes was reduced when the mutants were crossed to agol and piwi mutants. Our data suggest that hairpin RNA can induce phenotypic inheritance in Drosophila.

  1. Autosomal dominant inheritance of left ventricular outflow tract obstruction

    NARCIS (Netherlands)

    Wessels, Marjolein; Berger, Rudolphus; Frohn-Mulder, Ingrid M E; Roos-Hesselink, Jolien W; Hoogeboom, Jeanette J M; Mancini, Grazia S; Bartelings, Margot M; Krijger, Ronald de; Wladimiroff, Jury W; Niermeijer, Martinus F; Grossfeld, Paul; Willems, Patrick J


    Most nonsyndromic congenital heart malformations (CHMs) in humans are multifactorial in origin, although an increasing number of monogenic cases have been reported recently. We describe here four new families with presumed autosomal dominant inheritance of left ventricular outflow tract obstruction

  2. Regulation, cell differentiation and protein-based inheritance. (United States)

    Malagnac, Fabienne; Silar, Philippe


    Recent research using fungi as models provide new insight into the ability of regulatory networks to generate cellular states that are sufficiently stable to be faithfully transmitted to daughter cells, thereby generating epigenetic inheritance. Such protein-based inheritance is driven by infectious factors endowed with properties usually displayed by prions. We emphasize the contribution of regulatory networks to the emerging properties displayed by cells.

  3. Uniparental Inheritance and Replacement of Mitochondrial DNA in Neurospora Tetrasperma


    Lee, S B; Taylor, J. W.


    This study tested mechanisms proposed for maternal uniparental mitochondrial inheritance in Neurospora: (1) exclusion of conidial mitochondria by the specialized female reproductive structure, trichogyne, due to mating locus heterokaryon incompatibility and (2) mitochondrial input bias favoring the larger trichogyne over the smaller conidium. These mechanisms were tested by determining the modes of mitochondrial DNA (mtDNA) inheritance and transmission in the absence of mating locus heterokar...

  4. Dominant inheritance of overo spotting in paint horses. (United States)

    Bowling, A T


    Analysis of selected studbook records of the American Paint Horse Association, consisting of 687 foals sired by 13 overo stallions from non-overo mares, supports the inheritance of overo spotting as an autosomal dominant gene. More than one gene may control patterns registered as overo. Additional studies are necessary to explain the sporadic occurrence of overo spotting from nonspotted quarter horse parents and to confirm the inheritance of overo spotting in other breeds.

  5. Data Mining and Pattern Recognition Models for Identifying Inherited Diseases

    DEFF Research Database (Denmark)

    Iddamalgoda, Lahiru; Das, Partha S; Aponso, Achala;


    Data mining and pattern recognition methods reveal interesting findings in genetic studies, especially on how the genetic makeup is associated with inherited diseases. Although researchers have proposed various data mining models for biomedical approaches, there remains a challenge in accurately...... prioritizing the single nucleotide polymorphisms (SNP) associated with the disease. In this commentary, we review the state-of-art data mining and pattern recognition models for identifying inherited diseases and deliberate the need of binary classification- and scoring-based prioritization methods...

  6. Family networks and material inheritances: passing on the testimony

    Directory of Open Access Journals (Sweden)

    Marta Faria Patrão


    Full Text Available This study aims to deepen the knowledge about the process of material inheritance transmission in later life families, by studying the profiles of transmission of material legacy (what is transmitted, to whom, when and how?, the dynamics of support between donors and heirs and their influence on family satisfaction. Main results suggest that material inheritance is a normative process in later life families, involving the reorganization of the management of families’ material property and its transmission (passing on financial testimony.

  7. Genetic testing and counselling in inherited eye disease

    DEFF Research Database (Denmark)

    Brøndum-Nielsen, Karen; Jensen, Hanne; Timshel, Susanne


    Advances in genetics have made genetic testing in patients with inherited eye disease increasingly accessible, and the initiation of clinical intervention trials makes it increasingly clinically relevant. Based on a multidisciplinary collaboration between ophthalmologists and clinical geneticists......, the extensive register of families with monogenic inherited eye diseases at the National Eye Clinic of the Kennedy Center in Denmark provides a valuable asset waiting to be exploited in the global effort to reduce blindness caused by genetic defects....

  8. Flooding and Canopy Dynamics Shape the Demography of a Clonal Amazon Understorey Herb

    National Research Council Canada - National Science Library

    Matthias Schleuning; Vicky Huamán; Diethart Matthies


    .... We studied the influence of flooding and canopy gaps on the demography of the widespread clonal herb Heliconia metallica in 16 populations in the Peruvian Amazon over two wet and two dry seasons...

  9. Clonal Streptococcus equi subsp. zooepidemicus post breeding endometritis in thoroughbred broodmares

    DEFF Research Database (Denmark)

    Christoffersen, Mette; Söderlind, Maja; Rydemann Rudefalk, Sofia;

    was to investigate whether clonal or genetically distinct S. zooepidemicus strains isolated from mares with endometritis were associated with mare risk factors and the outcome of natural cover. Uterine swabs were obtained from mares with intrauterine fluid after natural cover (n=31) at thoroughbred stud farms....... zooepidemicus infection was associated with increased age, high parity and poor vulvar conformation. Mares with clonal infection had a low pregnancy rate (38%) compared with mares with two strains isolated (80%). In conclusion, the results indicate that clonal S. zooepidemicus endometritis is associated...... further characterized by pulsed-field gel electrophoresis (PFGE). In total S. zooepidemicus isolates from 18 mares were analyzed. The isolates from 13 mares showed a high genetic relatedness within each individual mare, whereas two genetically distinct strains were isolated in five mares. A clonal S...

  10. An atlas of B-cell clonal distribution in the human body. (United States)

    Meng, Wenzhao; Zhang, Bochao; Schwartz, Gregory W; Rosenfeld, Aaron M; Ren, Daqiu; Thome, Joseph J C; Carpenter, Dustin J; Matsuoka, Nobuhide; Lerner, Harvey; Friedman, Amy L; Granot, Tomer; Farber, Donna L; Shlomchik, Mark J; Hershberg, Uri; Luning Prak, Eline T


    B-cell responses result in clonal expansion, and can occur in a variety of tissues. To define how B-cell clones are distributed in the body, we sequenced 933,427 B-cell clonal lineages and mapped them to eight different anatomic compartments in six human organ donors. We show that large B-cell clones partition into two broad networks-one spans the blood, bone marrow, spleen and lung, while the other is restricted to tissues within the gastrointestinal (GI) tract (jejunum, ileum and colon). Notably, GI tract clones display extensive sharing of sequence variants among different portions of the tract and have higher frequencies of somatic hypermutation, suggesting extensive and serial rounds of clonal expansion and selection. Our findings provide an anatomic atlas of B-cell clonal lineages, their properties and tissue connections. This resource serves as a foundation for studies of tissue-based immunity, including vaccine responses, infections, autoimmunity and cancer.

  11. Implementation of Microfluidic Chip Electrophoresis for the Detection of B-cell Clonality

    Directory of Open Access Journals (Sweden)

    Vazan M


    Full Text Available Introduction: A clonal population of B-cells is defined as those cells arising from the mitotic division of a single somatic cell with the same rearrangement of immunoglobulin genes. This gives rise to DNA markers for each individual lymphoid cell and its progenies and enables us to study clonality in different B-cell malignancies using multiplex polymerase chain reaction - PCR. The BIOMED-2 protocol has been implemented for clonality detection in lymphoproliferative diseases and exploits multiplex PCR reaction, subsequently analyzed by heteroduplex analysis (HDA using polyacrylamide gel electrophoresis (PAGE. With the advent of miniaturization and automation of molecular biology methods, lab-on-chip technologies were developed and replace partially the conventional approaches. We tested device for microfluidic chip, which is used for B-cells clonality analysis, using a PCR reaction for three subregions called frameworks (FR of the immunoglobulin heavy locus (IGH gene.

  12. Novel R tools for analysis of genome-wide population genetic data with emphasis on clonality

    Directory of Open Access Journals (Sweden)

    Zhian N Kamvar


    Full Text Available To gain a detailed understanding of how plant microbes evolve and adapt to hosts, pesticides, and other factors, knowledge of the population dynamics and evolutionary history of populations is crucial. Plant pathogen populations are often clonal or partially clonal which requires different analytical tools. With the advent of high throughput sequencing technologies, obtaining genome-wide population genetic data has become easier than ever before. We previously contributed the R package poppr specifically addressing issues with analysis of clonal populations. In this paper we provide several significant extensions to poppr with a focus on large, genome-wide SNP data. Specifically, we provide several new functionalities including the new function mlg.filter to define clone boundaries allowing for inspection and definition of what is a clonal lineage, minimum spanning networks with reticulation, a sliding-window analysis of the index of association, modular bootstrapping of any genetic distance, and analyses across any level of hierarchies.

  13. Impact of CHK2-small interfering RNA on CpG ODN7909-enhanced radiosensitivity in lung cancer A549 cells


    Chen W; Liu XQ; Qiao TK; Yuan SJ


    Wei Chen,* Xiaoqun Liu,* Tiankui Qiao, Sujuan Yuan Department of Oncology, Jinshan Hospital, Fudan University, Shanghai, People's Republic of China*These authors contributed equally to this workObjective: To investigate the impact of checkpoint kinase 2 (CHK2)-small interfering RNA (CHK2-siRNA) on the enhancement of radiosensitivity by CpG oligodeoxynucleotide (ODN) 7909 in lung cancer A549 cells.Methods: The A549 cells were randomly divided into five groups: control, CpG, X-ray, CpG ...

  14. Familial epilepsy in Algeria: Clinical features and inheritance profiles. (United States)

    Chentouf, Amina; Dahdouh, Aïcha; Guipponi, Michel; Oubaiche, Mohand Laïd; Chaouch, Malika; Hamamy, Hanan; Antonarakis, Stylianos E


    To document the clinical characteristics and inheritance pattern of epilepsy in multigeneration Algerian families. Affected members from extended families with familial epilepsy were assessed at the University Hospital of Oran in Algeria. Available medical records, neurological examination, electroencephalography and imaging data were reviewed. The epilepsy type was classified according to the criteria of the International League Against Epilepsy and modes of inheritance were deduced from pedigree analysis. The study population included 40 probands; 23 male (57.5%) and 17 female subjects (42.5%). The mean age of seizure onset was 9.5 ± 6.1 years. According to seizure onset, 16 patients (40%) had focal seizures and 20 (50%) had generalized seizures. Seizure control was achieved for two patients (5%) for 10 years, while 28 (70%) were seizure-free for 3 months. Eleven patients (27.5%) had prior febrile seizures, 12 were diagnosed with psychiatric disorders and four families had syndromic epilepsy. The consanguinity rate among parents of affected was 50% with phenotypic concordance observed in 25 families (62.5%). Pedigree analysis suggested autosomal dominant (AD) inheritance with or without reduced penetrance in 18 families (45%), probable autosomal recessive (AR) inheritance in 14 families (35%), and an X-linked recessive inheritance in one family. This study reveals large Algerian families with multigenerational inheritance of epilepsy. Molecular testing such as exome sequencing would clarify the genetic basis of epilepsy in some of our families. Copyright © 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

  15. Clonal dominance among T-lymphocyte infiltrates in arthritis

    Energy Technology Data Exchange (ETDEWEB)

    Stamenkovic, I.; Stegagno, M.; Wright, K.A.; Krane, S.M.; Amento, E.P.; Colvin, R.B.; Duquesnoy, R.J.; Kurnick, J.T.


    Synovial membranes in patients with rheumatoid arthritis as well as other types of chronic destructive inflammatory arthritis contain infiltrates of activated T lymphocytes that probably contribute to the pathogenesis of the disease. In an effort to elucidate the nature of these infiltrates, interleukin 2 (IL-2)-responsive T lymphocytes were grown out of synovial fragments from 14 patients undergoing surgery for advanced destructive inflammatory joint disease. Eleven of the samples examined were from patients with classical rheumatoid arthritis, while three others were obtained from individuals with clinical osteoarthritis. Southern blot analysis of T-cell receptor (TCR) ..beta..-chain genes in 13 of 14 cultures showed distinct rearrangements, indicating that each culture was characterized by the predominance of a limited number of clones. T-cell populations from peripheral blood stimulated with a variety of activators and expanded with IL-2 did not demonstrate evidence of similar clonality in long-term culture. These results suggest that a limited number of activated T-cell clones predominate at the site of tissue injury in rheumatoid synovial membranes as well as in other types of destructive inflammatory joint disease. Further characterization of these T-cell clones may aid our understanding of the pathogenesis of these rheumatic disorders.

  16. Enforcement of reproductive synchrony via policing in a clonal ant. (United States)

    Teseo, Serafino; Kronauer, Daniel J C; Jaisson, Pierre; Châline, Nicolas


    In insect societies, worker policing controls genetic conflicts between individuals and increases colony efficiency. However, disentangling relatedness from colony-level effects is usually impossible. We studied policing in the parthenogenetic ant Cerapachys biroi, where genetic conflicts are absent due to clonality and reproduction is synchronized through stereotyped colony cycles. We show that larval cues regulate the cycles by suppressing ovarian activity and that individuals that fail to respond to these cues are policed and executed by their nestmates. These individuals are genetically identical to other colony members, confirming the absence of intracolonial genetic conflicts. At the same time, they bear distinct cuticular hydrocarbon profiles, which could serve as proximate recognition cues for policing. Policing in C. biroi keeps uncontrolled reproduction at bay and thereby maintains the colony-level phenotype. This study shows that policing can enforce adaptive colony-level phenotypes in societies with minimal or no potential genetic conflicts. In analogy to immunosurveillance on cancer cells in genetically homogeneous multicellular organisms, colony efficiency is improved via the control of individuals that do not respond properly to regulatory signals and compromise the functioning of the higher-level unit. Copyright © 2013 Elsevier Ltd. All rights reserved.

  17. Affected chromosome homeostasis and genomic instability of clonal yeast cultures. (United States)

    Adamczyk, Jagoda; Deregowska, Anna; Panek, Anita; Golec, Ewelina; Lewinska, Anna; Wnuk, Maciej


    Yeast cells originating from one single colony are considered genotypically and phenotypically identical. However, taking into account the cellular heterogeneity, it seems also important to monitor cell-to-cell variations within a clone population. In the present study, a comprehensive yeast karyotype screening was conducted using single chromosome comet assay. Chromosome-dependent and mutation-dependent changes in DNA (DNA with breaks or with abnormal replication intermediates) were studied using both single-gene deletion haploid mutants (bub1, bub2, mad1, tel1, rad1 and tor1) and diploid cells lacking one active gene of interest, namely BUB1/bub1, BUB2/bub2, MAD1/mad1, TEL1/tel1, RAD1/rad1 and TOR1/tor1 involved in the control of cell cycle progression, DNA repair and the regulation of longevity. Increased chromosome fragility and replication stress-mediated chromosome abnormalities were correlated with elevated incidence of genomic instability, namely aneuploid events-disomies, monosomies and to a lesser extent trisomies as judged by in situ comparative genomic hybridization (CGH). The tor1 longevity mutant with relatively balanced chromosome homeostasis was found the most genomically stable among analyzed mutants. During clonal yeast culture, spontaneously formed abnormal chromosome structures may stimulate changes in the ploidy state and, in turn, promote genomic heterogeneity. These alterations may be more accented in selected mutated genetic backgrounds, namely in yeast cells deficient in proper cell cycle regulation and DNA repair.

  18. Clonal cell populations unresponsive to radiosensitization induced by telomerase inhibition

    Energy Technology Data Exchange (ETDEWEB)

    Ju, Yeun-Jin; Shin, Hyun-Jin; Park, Jeong-Eun; Juhn, Kyoung-Mi; Woo, Seon Rang; Kim, Hee-Young; Han, Young-Hoon; Hwang, Sang-Gu; Hong, Sung-Hee; Kang, Chang-Mo [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul 139-706 (Korea, Republic of); Yoo, Young-Do [Laboratory of Molecular Cell Biology, Graduate School of Medicine, Korea University College of Medicine, Korea University, Seoul 136-705 (Korea, Republic of); Park, Won-Bong [Division of Natural Science, Seoul Women' s University, Seoul 139-774 (Korea, Republic of); Cho, Myung-Haing [Laboratory of Toxicology, College of Veterinary Medicine, Seoul National University, Seoul (Korea, Republic of); Park, Gil Hong, E-mail: [Department of Biochemistry, College of Medicine, Korea University, Seoul (Korea, Republic of); Lee, Kee-Ho, E-mail: [Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul 139-706 (Korea, Republic of)


    Research highlights: {yields} In our present manuscript, we have clearly showed an interesting but problematic obstacle of a radiosensitization strategy based on telomerase inhibition by showing that: Clonal population unresponsive to this radiosensitization occasionally arise. {yields} The telomere length of unsensitized clones was reduced, as was that of most sensitized clones. {yields} The unsensitized clones did not show chromosome end fusion which was noted in all sensitized clones. {yields} P53 status is not associated with the occurrence of unsensitized clone. {yields} Telomere end capping in unsensitized clone is operative even under telomerase deficiency. -- Abstract: A combination of a radiotherapeutic regimen with telomerase inhibition is valuable when tumor cells are to be sensitized to radiation. Here, we describe cell clones unresponsive to radiosensitization after telomere shortening. After extensive division of individual transformed clones of mTERC{sup -/-} cells, about 22% of clones were unresponsive to radiosensitization even though telomerase action was inhibited. The telomere lengths of unsensitized mTERC{sup -/-} clones were reduced, as were those of most sensitized clones. However, the unsensitized clones did not exhibit chromosomal end-to-end fusion to the extent noted in all sensitized clones. Thus, a defense mechanism preventing telomere erosion is operative even when telomeres become shorter under conditions of telomerase deficiency, and results in unresponsiveness to the radiosensitization generally mediated by telomere shortening.

  19. Detectable clonal mosaicism and its relationship to aging and cancer (United States)

    Jacobs, Kevin B; Yeager, Meredith; Zhou, Weiyin; Wacholder, Sholom; Wang, Zhaoming; Rodriguez-Santiago, Benjamin; Hutchinson, Amy; Deng, Xiang; Liu, Chenwei; Horner, Marie-Josephe; Cullen, Michael; Epstein, Caroline G; Burdett, Laurie; Dean, Michael C; Chatterjee, Nilanjan; Sampson, Joshua; Chung, Charles C; Kovaks, Joseph; Gapstur, Susan M; Stevens, Victoria L; Teras, Lauren T; Gaudet, Mia M; Albanes, Demetrius; Weinstein, Stephanie J; Virtamo, Jarmo; Taylor, Philip R; Freedman, Neal D; Abnet, Christian C; Goldstein, Alisa M; Hu, Nan; Yu, Kai; Yuan, Jian-Min; Liao, Linda; Ding, Ti; Qiao, You-Lin; Gao, Yu-Tang; Koh, Woon-Puay; Xiang, Yong-Bing; Tang, Ze-Zhong; Fan, Jin-Hu; Aldrich, Melinda C; Amos, Christopher; Blot, William J; Bock, Cathryn H; Gillanders, Elizabeth M; Harris, Curtis C; Haiman, Christopher A; Henderson, Brian E; Kolonel, Laurence N; Le Marchand, Loic; McNeill, Lorna H; Rybicki, Benjamin A; Schwartz, Ann G; Signorello, Lisa B; Spitz, Margaret R; Wiencke, John K; Wrensch, Margaret; Wu, Xifeng; Zanetti, Krista A; Ziegler, Regina G; Figueroa, Jonine D; Garcia-Closas, Montserrat; Malats, Nuria; Marenne, Gaelle; Prokunina-Olsson, Ludmila; Baris, Dalsu; Schwenn, Molly; Johnson, Alison; Landi, Maria Teresa; Goldin, Lynn; Consonni, Dario; Bertazzi, Pier Alberto; Rotunno, Melissa; Rajaraman, Preetha; Andersson, Ulrika; Freeman, Laura E Beane; Berg, Christine D; Buring, Julie E; Butler, Mary A; Carreon, Tania; Feychting, Maria; Ahlbom, Anders; Gaziano, J Michael; Giles, Graham G; Hallmans, Goran; Hankinson, Susan E; Hartge, Patricia; Henriksson, Roger; Inskip, Peter D; Johansen, Christoffer; Landgren, Annelie; McKean-Cowdin, Roberta; Michaud, Dominique S; Melin, Beatrice S; Peters, Ulrike; Ruder, Avima M; Sesso, Howard D; Severi, Gianluca; Shu, Xiao-Ou; Visvanathan, Kala; White, Emily; Wolk, Alicja; Zeleniuch-Jacquotte, Anne; Zheng, Wei; Silverman, Debra T; Kogevinas, Manolis; Gonzalez, Juan R; Villa, Olaya; Li, Donghui; Duell, Eric J; Risch, Harvey A; Olson, Sara H; Kooperberg, Charles; Wolpin, Brian M; Jiao, Li; Hassan, Manal; Wheeler, William; Arslan, Alan A; Bas Bueno-de-Mesquita, H; Fuchs, Charles S; Gallinger, Steven; Gross, Myron D; Holly, Elizabeth A; Klein, Alison P; LaCroix, Andrea; Mandelson, Margaret T; Petersen, Gloria; Boutron-Ruault, Marie-Christine; Bracci, Paige M; Canzian, Federico; Chang, Kenneth; Cotterchio, Michelle; Giovannucci, Edward L; Goggins, Michael; Bolton, Judith A Hoffman; Jenab, Mazda; Khaw, Kay-Tee; Krogh, Vittorio; Kurtz, Robert C; McWilliams, Robert R; Mendelsohn, Julie B; Rabe, Kari G; Riboli, Elio; Tjønneland, Anne; Tobias, Geoffrey S; Trichopoulos, Dimitrios; Elena, Joanne W; Yu, Herbert; Amundadottir, Laufey; Stolzenberg-Solomon, Rachael Z; Kraft, Peter; Schumacher, Fredrick; Stram, Daniel; Savage, Sharon A; Mirabello, Lisa; Andrulis, Irene L; Wunder, Jay S; García, Ana Patiño; Sierrasesúmaga, Luis; Barkauskas, Donald A; Gorlick, Richard G; Purdue, Mark; Chow, Wong-Ho; Moore, Lee E; Schwartz, Kendra L; Davis, Faith G; Hsing, Ann W; Berndt, Sonja I; Black, Amanda; Wentzensen, Nicolas; Brinton, Louise A; Lissowska, Jolanta; Peplonska, Beata; McGlynn, Katherine A; Cook, Michael B; Graubard, Barry I; Kratz, Christian P; Greene, Mark H; Erickson, Ralph L; Hunter, David J; Thomas, Gilles; Hoover, Robert N; Real, Francisco X; Fraumeni, Joseph F; Caporaso, Neil E; Tucker, Margaret; Rothman, Nathaniel; Pérez-Jurado, Luis A; Chanock, Stephen J


    In an analysis of 31,717 cancer cases and 26,136 cancer-free controls drawn from 13 genome-wide association studies (GWAS), we observed large chromosomal abnormalities in a subset of clones from DNA obtained from blood or buccal samples. Mosaic chromosomal abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of size >2 Mb were observed in autosomes of 517 individuals (0.89%) with abnormal cell proportions between 7% and 95%. In cancer-free individuals, the frequency increased with age; 0.23% under 50 and 1.91% between 75 and 79 (p=4.8×10−8). Mosaic abnormalities were more frequent in individuals with solid-tumors (0.97% versus 0.74% in cancer-free individuals, OR=1.25, p=0.016), with a stronger association for cases who had DNA collected prior to diagnosis or treatment (OR=1.45, p=0.0005). Detectable clonal mosaicism was common in individuals for whom DNA was collected at least one year prior to diagnosis of leukemia compared to cancer-free individuals (OR=35.4, p=3.8×10−11). These findings underscore the importance of the role and time-dependent nature of somatic events in the etiology of cancer and other late-onset diseases. PMID:22561519

  20. CpG promoter methylation status is not a prognostic indicator of gene expression in beryllium challenge. (United States)

    Tooker, Brian C; Ozawa, Katherine; Newman, Lee S


    Individuals exposed to beryllium (Be) may develop Be sensitization (BeS) and progress to chronic beryllium disease (CBD). Recent studies with other metal antigens suggest epigenetic mechanisms may be involved in inflammatory disease processes, including granulomatous lung disorders and that a number of metal cations alter gene methylation. The objective of this study was to determine if Be can exert an epigenetic effect on gene expression by altering methylation in the promoter region of specific genes known to be involved in Be antigen-mediated gene expression. To investigate this objective, three macrophage tumor mouse cell lines known to differentially produce tumor necrosis factor (TNF)-α, but not interferon (IFN)-γ, in response to Be antigen were cultured with Be or controls. Following challenges, ELISA were performed to quantify induced TNFα and IFNγ expression. Bisulfate-converted DNA was evaluated by pyrosequencing to quantify CpG methylation within the promoters of TNFα and IFNγ. Be-challenged H36.12J cells expressed higher levels of TNFα compared to either H36.12E cells or P388D.1 cells. However, there were no variations in TNFα promoter CpG methylation levels between cell lines at the six CpG sites tested. H36.12J cell TNFα expression was shown to be metal-specific by the induction of significantly more TNFα when exposed to Be than when exposed to aluminum sulfate, or nickel (II) chloride, but not when exposed to cobalt (II) chloride. However, H36.12J cell methylation levels at the six CpG sites examined in the TNFα promoter did not correlate with cytokine expression differences. Nonetheless, all three cell lines had significantly more promoter methylation at the six CpG sites investigated within the IFNγ promoter (a gene that is not expressed) when compared to the six CpG sites investigated in the TNFα promoter, regardless of treatment condition (p beryllium had no impact on promoter methylation status, despite its ability to induce pro

  1. PyClone: statistical inference of clonal population structure in cancer. (United States)

    Roth, Andrew; Khattra, Jaswinder; Yap, Damian; Wan, Adrian; Laks, Emma; Biele, Justina; Ha, Gavin; Aparicio, Samuel; Bouchard-Côté, Alexandre; Shah, Sohrab P


    We introduce PyClone, a statistical model for inference of clonal population structures in cancers. PyClone is a Bayesian clustering method for grouping sets of deeply sequenced somatic mutations into putative clonal clusters while estimating their cellular prevalences and accounting for allelic imbalances introduced by segmental copy-number changes and normal-cell contamination. Single-cell sequencing validation demonstrates PyClone's accuracy.

  2. Mutational Profiling Can Establish Clonal or Independent Origin in Synchronous Bilateral Breast and Other Tumors.

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    Lei Bao

    Full Text Available Synchronous tumors can be independent primary tumors or a primary-metastatic (clonal pair, which may have clinical implications. Mutational profiling of tumor DNA is increasingly common in the clinic. We investigated whether mutational profiling can distinguish independent from clonal tumors in breast and other cancers, using a carefully defined test based on the Clonal Likelihood Score (CLS = 100 x # shared high confidence (HC mutations/ # total HC mutations.Statistical properties of a formal test using the CLS were investigated. A high CLS is evidence in favor of clonality; the test is implemented as a one-sided binomial test of proportions. Test parameters were empirically determined using 16,422 independent breast tumor pairs and 15 primary-metastatic tumor pairs from 10 cancer types using The Cancer Genome Atlas.We validated performance of the test with its established parameters, using five published data sets comprising 15,758 known independent tumor pairs (maximum CLS = 4.1%, minimum p-value = 0.48 and 283 known tumor clonal pairs (minimum CLS 13%, maximum p-value 0.99, supporting independence. A plausible molecular mechanism for the shift from hormone receptor positive to triple negative was identified in the clonal pair.We have developed the statistical properties of a carefully defined Clonal Likelihood Score test from mutational profiling of tumor DNA. Under identified conditions, the test appears to reliably distinguish between synchronous tumors of clonal and of independent origin in several cancer types. This approach may have scientific and clinical utility.

  3. Resource heterogeneity, soil fertility, and species diversity: effects of clonal species on plant communities. (United States)

    Eilts, J Alexander; Mittelbach, Gary G; Reynolds, Heather L; Gross, Katherine L


    Spatial heterogeneity in soil resources is widely thought to promote plant species coexistence, and this mechanism figures prominently in resource-ratio models of competition. However, most experimental studies have found that nutrient enhancements depress diversity regardless of whether nutrients are uniformly or heterogeneously applied. This mismatch between theory and empirical pattern is potentially due to an interaction between plant size and the scale of resource heterogeneity. Clonal plants that spread vegetatively via rhizomes or stolons can grow large and may integrate across resource patches, thus reducing the positive effect of small-scale resource heterogeneity on plant species richness. Many rhizomatous clonal species respond strongly to increased soil fertility, and they have been hypothesized to drive the descending arm of the hump-shaped productivity-diversity relationship in grasslands. We tested whether clonals reduce species richness in a grassland community by manipulating nutrient heterogeneity, soil fertility, and the presence of rhizomatous clonal species in a 6-year field experiment. We found strong and consistent negative effects of clonals on species richness. These effects were greatest at high fertility and when soil resources were applied at a scale at which rhizomatous clonals could integrate across resource patches. Thus, we find support for the hypothesis that plant size and resource heterogeneity interact to determine species diversity.

  4. The clonal and mutational evolution spectrum of primary triple negative breast cancers (United States)

    Shah, Sohrab P.; Roth, Andrew; Goya, Rodrigo; Oloumi, Arusha; Ha, Gavin; Zhao, Yongjun; Turashvili, Gulisa; Ding, Jiarui; Tse, Kane; Haffari, Gholamreza; Bashashati, Ali; Prentice, Leah M.; Khattra, Jaswinder; Burleigh, Angela; Yap, Damian; Bernard, Virginie; McPherson, Andrew; Shumansky, Karey; Crisan, Anamaria; Giuliany, Ryan; Heravi-Moussavi, Alireza; Rosner, Jamie; Lai, Daniel; Birol, Inanc; Varhol, Richard; Tam, Angela; Dhalla, Noreen; Zeng, Thomas; Ma, Kevin; Chan, Simon; Griffith, Malachi; Moradian, Annie; Grace Cheng, S.-W.; Morin, Gregg B.; Watson, Peter; Gelmon, Karen; Chia, Stephen; Chin, Suet-Feung; Curtis, Christina; Rueda, Oscar; Pharoah, Paul D; Damaraju, Sambasivarao; Mackey, John; Hoon, Kelly; Harkins, Timothy; Tadigotla, Vasisht; Sigaroudinia, Mahvash; Gascard, Philippe; Tlsty, Thea; Costello, Joseph F; Meyer, Irmtraud M; Eaves, Connie J; Wasserman, Wyeth W; Jones, Steven; Huntsman, David; Hirst, Martin; Caldas, Carlos; Marra, Marco A; Aparicio, Samuel


    Primary triple negative breast cancers (TNBC) represent approximately 16% of all breast cancers1 and are a tumour type defined by exclusion, for which comprehensive landscapes of somatic mutation have not been determined. Here we show in 104 early TNBC cases, that at the time of diagnosis these cancers exhibit a wide and continuous spectrum of genomic evolution, with some exhibiting only a handful of somatic aberrations in a few pathways, whereas others contain hundreds of somatic events and multiple pathways implicated. Integration with matched whole transcriptome sequence data revealed that only ~36% of mutations are expressed. By examining single nucleotide variant (SNV) allelic abundance derived from deep re-sequencing (median >20,000 fold) measurements in 2414 somatic mutations, we determine for the first time in an epithelial tumour, the relative abundance of clonal genotypes among cases in the population. We show that TNBC vary widely and continuously in their clonal frequencies at the time of diagnosis, with basal subtype TNBC2,3 exhibiting more variation than non-basal TNBC. Although p53 and PIK3CA/PTEN somatic mutations appear clonally dominant compared with other pathways, in some tumours their clonal frequencies are incompatible with founder status. Mutations in cytoskeletal and cell shape/motility proteins occurred at lower clonal frequencies, suggesting they occurred later during tumour progression. Taken together our results show that future attempts to dissect the biology and therapeutic responses of TNBC will require the determination of individual tumour clonal genotypes. PMID:22495314

  5. Plant clonal integration mediates the horizontal redistribution of soil resources, benefiting neighbouring plants

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    Xuehua eYe


    Full Text Available Resources such as water taken up by plants can be released into soils through hydraulic redistribution and can also be translocated by clonal integration within a plant clonal network. We hypothesized that the resources from one (donor microsite could be translocated within a clonal network, released into different (recipient microsites and subsequently used by neighbour plants in the recipient microsite. To test these hypotheses, we conducted two experiments in which connected and disconnected ramet pairs of Potentilla anserina were grown under both homogeneous and heterogeneous water regimes, with seedlings of Artemisia ordosica as neighbours. The isotopes [15N] and deuterium were used to trace the translocation of nitrogen and water, respectively, within the clonal network. The water and nitrogen taken up by P. anserina ramets in the donor microsite were translocated into the connected ramets in the recipient microsites. Most notably, portions of the translocated water and nitrogen were released into the recipient microsite and were used by the neighbouring A. ordosica, which increased growth of the neighbouring A. ordosica significantly. Therefore, our hypotheses were supported, and plant clonal integration mediated the horizontal hydraulic redistribution of resources, thus benefiting neighbouring plants. Such a plant clonal integration-mediated resource redistribution in horizontal space may have substantial effects on the interspecific relations and composition of the community and consequently on ecosystem processes.

  6. Plant Clonal Integration Mediates the Horizontal Redistribution of Soil Resources, Benefiting Neighboring Plants. (United States)

    Ye, Xue-Hua; Zhang, Ya-Lin; Liu, Zhi-Lan; Gao, Shu-Qin; Song, Yao-Bin; Liu, Feng-Hong; Dong, Ming


    Resources such as water taken up by plants can be released into soils through hydraulic redistribution and can also be translocated by clonal integration within a plant clonal network. We hypothesized that the resources from one (donor) microsite could be translocated within a clonal network, released into different (recipient) microsites and subsequently used by neighbor plants in the recipient microsite. To test these hypotheses, we conducted two experiments in which connected and disconnected ramet pairs of Potentilla anserina were grown under both homogeneous and heterogeneous water regimes, with seedlings of Artemisia ordosica as neighbors. The isotopes [(15)N] and deuterium were used to trace the translocation of nitrogen and water, respectively, within the clonal network. The water and nitrogen taken up by P. anserina ramets in the donor microsite were translocated into the connected ramets in the recipient microsites. Most notably, portions of the translocated water and nitrogen were released into the recipient microsite and were used by the neighboring A. ordosica, which increased growth of the neighboring A. ordosica significantly. Therefore, our hypotheses were supported, and plant clonal integration mediated the horizontal hydraulic redistribution of resources, thus benefiting neighboring plants. Such a plant clonal integration-mediated resource redistribution in horizontal space may have substantial effects on the interspecific relations and composition of the community and consequently on ecosystem processes.

  7. CpG motifs present in bacteria DNA rapidly induce lymphocytes to secrete interleukin 6, interleukin 12, and interferon gamma. (United States)

    Klinman, D M; Yi, A K; Beaucage, S L; Conover, J; Krieg, A M


    Bacterial infection stimulates the host to mount a rapid inflammatory response. A 6-base DNA motif consisting of an unmethylated CpG dinucleotide flanked by two 5' purines and two 3' pyrimidines was shown to contribute to this response by inducing polygonal B-cell activation. This stimulatory motif is 20 times more common in the DNA of bacteria than higher vertebrates. The current work shows that the same motif induces the rapid and coordinated secretion of interleukin (IL) 6, IL-12, and interferon gamma (but not IL-2, IL-3, IL-4, IL-5, or IL-10) in vivo and in vitro. Stimulatory CpG DNA motifs induced B, T, and natural killer cells to secrete cytokine more effectively than did lipopolysaccharide. Thus, immune recognition of bacterial DNA may contribute to the cytokine, as well as the antibody production characteristic of an innate inflammatory response.

  8. Generation and Inheritance of Targeted Mutations in Potato (Solanum tuberosum L. Using the CRISPR/Cas System.

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    Nathaniel M Butler

    Full Text Available Genome editing using sequence-specific nucleases (SSNs offers an alternative approach to conventional genetic engineering and an opportunity to extend the benefits of genetic engineering in agriculture. Currently available SSN platforms, such as zinc finger nucleases (ZFNs, transcription activator-like effector nucleases (TALENs, and CRISPR/Cas (clustered regularly interspaced short palindromic repeats (CRISPR/CRISPR-associated systems (Cas have been used in a range of plant species for targeted mutagenesis via non-homologous end joining (NHEJ are just beginning to be explored in crops such as potato (Solanum tuberosum Group Tuberosum L.. In this study, CRISPR/Cas reagents expressing one of two single-guide RNA (sgRNA targeting the potato ACETOLACTATE SYNTHASE1 (StALS1 gene were tested for inducing targeted mutations in callus and stable events of diploid and tetraploid potato using Agrobacterium-mediated transformation with either a conventional T-DNA or a modified geminivirus T-DNA. The percentage of primary events with targeted mutations ranged from 3-60% per transformation and from 0-29% above an expected threshold based on the number of ALS alleles. Primary events with targeted mutation frequencies above the expected threshold were used for mutation cloning and inheritance studies using clonal propagation and crosses or selfing. Four of the nine primary events used for mutation cloning had more than one mutation type, and eight primary events contained targeted mutations that were maintained across clonal generations. Somatic mutations were most evident in the diploid background with three of the four primary events having more than two mutation types at a single ALS locus. Conversely, in the tetraploid background, four of the five candidates carried only one mutation type. Single targeted mutations were inherited through the germline of both diploid and tetraploid primary events with transmission percentages ranging from 87-100%. This

  9. A transfer function approach to measuring cell inheritance

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    Errington Rachel J


    Full Text Available Abstract Background The inheritance of cellular material between parent and daughter cells during mitosis is highly influential in defining the properties of the cell and therefore the population lineage. This is of particular relevance when studying cell population evolution to assess the impact of a disease or the perturbation due to a drug treatment. The usual technique to investigate inheritance is to use time-lapse microscopy with an appropriate biological marker, however, this is time consuming and the number of inheritance events captured are too low to be statistically meaningful. Results Here we demonstrate the use of a high throughput fluorescence measurement technique e.g. flow cytometry, to measure the fluorescence from quantum dot markers which can be used to target particular cellular sites. By relating, the fluorescence intensity measured between two time intervals to a transfer function we are able to deconvolve the inheritance of cellular material during mitosis. To demonstrate our methodology we use CdTe/ZnS quantum dots to measure the ratio of endosomes inherited by the two daughter cells during mitosis in the U2-OS, human osteoscarcoma cell line. The ratio determined is in excellent agreement with results obtained previously using a more complex and computational intensive bespoke stochastic model. Conclusions The use of a transfer function approach allows us to utilise high throughput measurement of large cell populations to derive statistically relevant measurements of the inheritance of cellular material. This approach can be used to measure the inheritance of organelles, proteins etc. and also particles introduced to cells for drug delivery.

  10. Co-administration of CpG oligonucleotides enhances the late affinity maturation process of human anti-hepatitis B vaccine response. (United States)

    Siegrist, Claire-Anne; Pihlgren, Maria; Tougne, Chantal; Efler, Sue M; Morris, Mary Lou; AlAdhami, Mohammed J; Cameron, D William; Cooper, Curtis L; Heathcote, Jenny; Davis, Heather L; Lambert, Paul-Henri


    We assessed the avidity maturation process elicited by human immunization with alum-adsorbed HBsAg alone or with a novel adjuvant containing CpG motifs (CpG 7909). Mean avidity indexes and distribution of low- and high-avidity anti-HBs indicated that avidity maturation essentially takes place late after priming. CpG 7909 markedly enhanced this affinity maturation process, increasing the pool of high-avidity antibodies. The influence of CpG 7909 was antigen-specific, isotype-specific and distinct from the influence on anti-HBs production, as avidity did not correlate with anti-HBs IgG titers. This is the first demonstration that a novel human adjuvant may induce antibodies with higher antigen-binding affinity.

  11. Expression profiling of clonal lymphocyte cell cultures from Rett syndrome patients (United States)

    More than 85% of Rett syndrome (RTT) patients have heterozygous mutations in the X-linked MECP2 gene which encodes methyl-CpG-binding protein 2, a transcriptional repressor that binds methylated CpG sites. Because MECP2 is subject to X chromosome inactivation (XCI), girls with RTT express either the...

  12. Genome-wide methylation analysis identifies differentially methylated CpG loci associated with severe obesity in childhood. (United States)

    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


    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.

  13. Racial Differences in DNA-Methylation of CpG Sites Within Preterm-Promoting Genes and Gene Variants. (United States)

    Salihu, H M; Das, R; Morton, L; Huang, H; Paothong, A; Wilson, R E; Aliyu, M H; Salemi, J L; Marty, P J


    Objective To evaluate the role DNA methylation may play in genes associated with preterm birth for higher rates of preterm births in African-American women. Methods Fetal cord blood samples from births collected at delivery and maternal demographic and medical information were used in a cross-sectional study to examine fetal DNA methylation of genes implicated in preterm birth among black and non-black infants. Allele-specific DNA methylation analysis was performed using a methylation bead array. Targeted maximum likelihood estimation was applied to examine the relationship between race and fetal DNA methylation of candidate preterm birth genes. Receiver-operating characteristic analyses were then conducted to validate the CpG site methylation marker within the two racial groups. Bootstrapping, a method of validation and replication, was employed. Results 42 CpG sites were screened within 20 candidate gene variants reported consistently in the literature as being associated with preterm birth. Of these, three CpG sites on TNFAIP8 and PON1 genes (corresponding to: cg23917399; cg07086380; and cg07404485, respectively) were significantly differentially methylated between black and non-black individuals. The three CpG sites showed lower methylation status among infants of black women. Bootstrapping validated and replicated results. Conclusion for Practice Our study identified significant differences in levels of methylation on specific genes between black and non-black individuals. Understanding the genetic/epigenetic mechanisms that lead to preterm birth may lead to enhanced prevention strategies to reduce morbidity and mortality by eventually providing a means to identify individuals with a genetic predisposition to preterm labor.

  14. Hypomethylation of proximal CpG motif of interleukin-10 promoter regulates its expression in human rheumatoid arthritis

    Institute of Scientific and Technical Information of China (English)

    Li-hong FU; Chun-ling MA; Bin CONG; Shu-jin LI; Hai-ying CHEN; Jing-ge ZHANG


    Aim:The promoter of human interleukin-10 (IL10),a cytokine crucial for suppressing inflammation and regulating immune responses,contains an interspecies-conserved sequence with CpG motifs.The aim of this study was to investigate whether methylation of CpG motifs could regulate the expression of IL10 in rheumatoid arthritis (RA).Methods:Bioinformatic analysis was conducted to identify the interspecies-conserved sequence in human,macaque and mouse IL10 genes.Peripheral blood mononuclear cells (PBMCs) from 20 RA patients and 20 health controls were collected.The PBMCs from 6 patients were cultured in the presence or absence of 5-azacytidine (5 μmol/L).The mRNA and protein levels of IL10 were examined using RT-PCR and ELISA,respectively.The methylation of CpGs in the IL10 promoter was determined by pyrosequencing.Chromatin immunoprecipitation (CHIP) assays were performed to detect the cyclic AMP response element-binding protein (CREB)-DNA interactions.Results:One interspecies-conserved sequence was found within the IL10 promoter.The upstream CpGs at -408,-387,-385,and -355 bp were hypermethylated in PBMCs from both the RA patients and healthy controls.In contrast,the proximal CpG at -145 was hypomethylated to much more extent in the RA patients than in the healthy controls (P=0.016),which was correlated with higher IL10 mRNA and serum levels.In the 5-azacytidine-treated PBMCs,the CpG motifs were demethylated,and the expression levels of IL10 mRNA and protein was significantly increased.CHIP assays revealed increased phospho-CREB binding to the IL10 promoter.Conclusion:The methylation of the proximal CpGs in the IL10 promoter may regulate gene transcription in RA.

  15. In vivo control of CpG and non-CpG DNA methylation by DNA methyltransferases.

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    Julia Arand


    Full Text Available The enzymatic control of the setting and maintenance of symmetric and non-symmetric DNA methylation patterns in a particular genome context is not well understood. Here, we describe a comprehensive analysis of DNA methylation patterns generated by high resolution sequencing of hairpin-bisulfite amplicons of selected single copy genes and repetitive elements (LINE1, B1, IAP-LTR-retrotransposons, and major satellites. The analysis unambiguously identifies a substantial amount of regional incomplete methylation maintenance, i.e. hemimethylated CpG positions, with variant degrees among cell types. Moreover, non-CpG cytosine methylation is confined to ESCs and exclusively catalysed by Dnmt3a and Dnmt3b. This sequence position-, cell type-, and region-dependent non-CpG methylation is strongly linked to neighboring CpG methylation and requires the presence of Dnmt3L. The generation of a comprehensive data set of 146,000 CpG dyads was used to apply and develop parameter estimated hidden Markov models (HMM to calculate the relative contribution of DNA methyltransferases (Dnmts for de novo and maintenance DNA methylation. The comparative modelling included wild-type ESCs and mutant ESCs deficient for Dnmt1, Dnmt3a, Dnmt3b, or Dnmt3a/3b, respectively. The HMM analysis identifies a considerable de novo methylation activity for Dnmt1 at certain repetitive elements and single copy sequences. Dnmt3a and Dnmt3b contribute de novo function. However, both enzymes are also essential to maintain symmetrical CpG methylation at distinct repetitive and single copy sequences in ESCs.

  16. DNA methylation-based age prediction from saliva: High age predictability by combination of 7 CpG markers. (United States)

    Hong, Sae Rom; Jung, Sang-Eun; Lee, Eun Hee; Shin, Kyoung-Jin; Yang, Woo Ick; Lee, Hwan Young


    DNA methylation is currently one of the most promising age-predictive biomarkers. Many studies have reported DNA methylation-based age predictive models, but most of these are based on DNA methylation patterns from blood. Only a few studies have examined age-predictive DNA patterns in saliva, which is one of the most frequently-encountered body fluids at crime scenes. In this study, we generated genome-wide DNA methylation profiles of saliva from 54 individuals and identified CpG markers that showed a high correlation between methylation and age. Because the age-associated marker candidates from saliva differed from those of blood, we investigated DNA methylation patterns of 6 age-associated CpG marker candidates (cg00481951, cg19671120, cg14361627, cg08928145, cg12757011, and cg07547549 of the SST, CNGA3, KLF14, TSSK6, TBR1, and SLC12A5 genes, respectively) in addition to a cell type-specific CpG marker (cg18384097 of the PTPN7 gene) in an independent set of saliva samples obtained from 226 individuals aged 18 to 65 years. Multiplex methylation SNaPshot reactions were used to generate the data. We then generated a linear regression model with age information and the methylation profile from the 113 training samples. The model exhibited a 94.5% correlation between predicted and chronological age with a mean absolute deviation (MAD) from chronological age of 3.13 years. In subsequent validation using 113 test samples, we also observed a high correlation between predicted and chronological age (Spearman's rho=0.952, MAD from chronological age=3.15years). The model composed of 7 selected CpG sites enabled age prediction in saliva with high accuracy, which will be useful in saliva analysis for investigative leads. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Correlating CpG islands, motifs, and sequence variants in human chromosome 21

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    Cercone Nick


    Full Text Available Abstract Background CpG islands are important regions in DNA. They usually appear at the 5’ end of genes containing GC-rich dinucleotides. When DNA methylation occurs, gene regulation is affected and it sometimes leads to carcinogenesis. We propose a new detection program using a hidden-markov model alongside the Viterbi algorithm. Methods Our solution provides a graphical user interface not seen in many of the other CGI detection programs and we unify the detection and analysis under one program to allow researchers to scan a genetic sequence, detect the significant CGIs, and analyze the sequence once the scan is complete for any noteworthy findings. Results Using human chromosome 21, we show that our algorithm finds a significant number of CGIs. Running an analysis on a dataset of promoters discovered that the characteristics of methylated and unmethylated CGIs are significantly different. Finally, we detected significantly different motifs between methylated and unmethylated CGI promoters using MEME and MAST. Conclusions Developing this new tool for the community using powerful algorithms has shown that combining analysis with CGI detection will improve the continued research within the field of epigenetics.

  18. Prognostic significance of CpG island methylator phenotype in surgically resected small cell lung carcinoma. (United States)

    Saito, Yuichi; Nagae, Genta; Motoi, Noriko; Miyauchi, Eisaku; Ninomiya, Hironori; Uehara, Hirofumi; Mun, Mingyon; Okumura, Sakae; Ohyanagi, Fumiyoshi; Nishio, Makoto; Satoh, Yukitoshi; Aburatani, Hiroyuki; Ishikawa, Yuichi


    Methylation is closely involved in the development of various carcinomas. However, few datasets are available for small cell lung cancer (SCLC) due to the scarcity of fresh tumor samples. The aim of the present study is to clarify relationships between clinicopathological features and results of the comprehensive genome-wide methylation profile of SCLC. We investigated the genome-wide DNA methylation status of 28 tumor and 13 normal lung tissues, and gene expression profiling of 25 SCLC tissues. Following unsupervised hierarchical clustering and non-negative matrix factorization, gene ontology analysis was performed. Clustering of SCLC led to the important identification of a CpG island methylator phenotype (CIMP) of the tumor, with a significantly poorer prognosis (P = 0.002). Multivariate analyses revealed that postoperative chemotherapy and non-CIMP were significantly good prognostic factors. Ontology analyses suggested that the extrinsic apoptosis pathway was suppressed, including TNFRSF1A, TNFRSF10A and TRADD in CIMP tumors. Here we revealed that CIMP was an important prognostic factor for resected SCLC. Delineation of this phenotype may also be useful for the development of novel apoptosis-related chemotherapeutic agents for treatment of the aggressive tumor.

  19. Predicting DNA Methylation State of CpG Dinucleotide Using Genome Topological Features and Deep Networks. (United States)

    Wang, Yiheng; Liu, Tong; Xu, Dong; Shi, Huidong; Zhang, Chaoyang; Mo, Yin-Yuan; Wang, Zheng


    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

  20. Incorrect DNA methylation of the DAZL promoter CpG island associates with defective human sperm† (United States)

    Navarro-Costa, Paulo; Nogueira, Paulo; Carvalho, Marta; Leal, Fernanda; Cordeiro, Isabel; Calhaz-Jorge, Carlos; Gonçalves, João; Plancha, Carlos E.


    BACKGROUND Successful gametogenesis requires the establishment of an appropriate epigenetic state in developing germ cells. Nevertheless, an association between abnormal spermatogenesis and epigenetic disturbances in germline-specific genes remains to be demonstrated. METHODS In this study, the DNA methylation pattern of the promoter CpG island (CGI) of two germline regulator genes—DAZL and DAZ, was characterized by bisulphite genomic sequencing in quality-fractioned ejaculated sperm populations from normozoospermic (NZ) and oligoasthenoteratozoospermic (OAT) men. RESULTS OAT patients display increased methylation defects in the DAZL promoter CGI when compared with NZ controls. Such differences are recorded when analyzing sperm fractions enriched either in normal or defective germ cells (P< 0.001 in both cases). Significant differences in DNA methylation profiles are also observable when comparing the qualitatively distinct germ cell fractions inside the NZ and OAT groups (P= 0.003 and P= 0.007, respectively). Contrastingly, the unmethylation pattern of the DAZ promoter CGI remains correctly established in all experimental groups. CONCLUSIONS An association between disrupted DNA methylation of a key spermatogenesis gene and abnormal human sperm is described here for the first time. These results suggest that incorrect epigenetic marks in germline genes may be correlated with male gametogenic defects. PMID:20685756

  1. Impact of CHK2-small interfering RNA on CpG ODN7909-enhanced radiosensitivity in lung cancer A549 cells

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    Chen W


    Full Text Available Wei Chen,* Xiaoqun Liu,* Tiankui Qiao, Sujuan Yuan Department of Oncology, Jinshan Hospital, Fudan University, Shanghai, People's Republic of China*These authors contributed equally to this workObjective: To investigate the impact of checkpoint kinase 2 (CHK2-small interfering RNA (CHK2-siRNA on the enhancement of radiosensitivity by CpG oligodeoxynucleotide (ODN 7909 in lung cancer A549 cells.Methods: The A549 cells were randomly divided into five groups: control, CpG, X-ray, CpG + X-ray, and CHK2-siRNA + CpG + X-ray. Cell colonization was observed using inverted microscopy. Cell cycle and apoptosis were analyzed by flow cytometry. CHK2 expression was detected by Western blot. CHK2-siRNA was adopted to silence the expression of CHK2.Results: The level of CHK2 phosphorylation was higher in the CpG + X-ray group than in the X-ray group. Increases in G2/mitotic (M phase arrest and apoptosis and a decrease of cell survival rate in the CpG + X-ray group were statistically significant (P < 0.05 when compared with the CHK2-siRNA + CpG + X-ray group in which the expression of CHK2 was obviously inhibited. The combination of CpG ODN7909 and X-ray irradiation was found to enhance the mitotic death of A549 cells. The sensitization enhancement ratio of mean death dose (D0 was 1.42 in the CpG + X-ray group, which was higher than that of the CHK2-siRNA + CpG + X-ray group, in which D0 was 1.05.Conclusion: To a certain extent, the impact of a combination of CpG ODN7909 and X-ray on G2/M phase arrest, apoptosis, and rate of cell survival was attenuated by CHK2-siRNA in human lung adenocarcinoma A549 cells, indicating that increased phosphorylation of CHK2 might be a radiosensitive pathway.Keywords: oligodeoxynucleotide, checkpoint kinase 2, mitotic death, apoptosis, X-ray

  2. Pityriasis lichenoides: a clonal T-cell lymphoproliferative disorder. (United States)

    Magro, Cynthia; Crowson, A Neil; Kovatich, Al; Burns, Frank


    Pityriasis lichenoides (PL) is a papulosquamous disorder often considered a form of reactive dermatosis and classified with small plaque parapsoriasis (digitate dermatosis). However, some patients with PL have developed large plaque parapsoriasis (LPP) and mycosis fungoides (MF), and lymphoid atypia and T-cell clonality have been reported in lesions of PL. We set out to explore the possibility that PL is a form of T-cell dyscrasia. Cases were selected by natural language search from an outpatient dermatopathology database; 35 cases were reviewed and clinicians and patients were contacted. Hematoxylin and eosin-stained sections were examined and immunophenotyping was carried out on paraffin-embedded, formalin-fixed tissue using antibodies to CD2, CD3, CD4, CD5, CD7, CD8, CD20, CD30, and CD56. In paraffin-embedded tissue, T-cell receptor (TCR)-gamma chain rearrangement was sought through polymerase chain reaction single stranded conformational polymorphism analysis. There were 14 males and 21 females with a mean age of 40 years held clinically to have PL chronica (PLC) (28 cases) and/or PL et varioliformis acuta (PLEVA) (7 cases). Five patients developed large atrophic poikilodermatous and/or annular plaques compatible with MF and/or LPP in a background of typical PLC. All biopsies showed tropism of lymphocytes to an epidermis manifesting psoriasiform hyperplasia, dyskeratosis, parakeratosis, and intraepithelial collections of Langerhans' cells and lymphocytes mimicking Pautrier's microabascesses. Epidermal atrophy, dermal fibroplasia, poikilodermatous alterations, and a dominance of intraepidermal cerebriform cells were seen only in patients with chronic persistent disease (i.e., PLC) and in some cases corresponded with clinical progression to MF. All cases had a T cell-dominant infiltrate, with a CD7 deletion in 21 of 32 biopsies examined; the CD7-negative cells were typically the largest and most atypical forms, often in a cohesive array within the upper layers of

  3. The Staphylococcus aureus lineage-specific markers collagen adhesin and toxic shock syndrome toxin 1 distinguish multilocus sequence typing clonal complexes within spa clonal complexes

    NARCIS (Netherlands)

    Deurenberg, Ruud H; Rijnders, Michelle I A; Sebastian, Silvie; Welling, Maaike A; Beisser, Patrick S; Stobberingh, Ellen E


    Spa typing/based upon repeat pattern (BURP) sometimes cannot differentiate multilocus sequence typing (MLST) clonal complexes (CCs) within spa-CCs. It has been observed previously that virulence factors, such as collagen adhesin (CNA) and toxic shock syndrome toxin 1 (TSST-1), are associated with

  4. The prognostic value of clonal heterogeneity and quantitative assessment of plasma circulating clonal IG-VDJ sequences at diagnosis in patients with follicular lymphoma (United States)

    Sarkozy, Clémentine; Huet, Sarah; Carlton, Victoria E.H; Fabiani, Bettina; Delmer, Alain; Jardin, Fabrice; Delfau-Larue, Marie-Helene; Hacini, Maya; Ribrag, Vincent; Guidez, Stéphanie; Faham, Malek; Salles, Gilles


    Recent advances in next-generation sequencing (NGS) have enabled the quantitation of circulating tumour DNA (ctDNA) encoding the clonal rearranged V(D)J immunoglobulin locus. We aimed to evaluate the clonal heterogeneity of follicular lymphoma (FL) in the tumour and the plasma at diagnosis and to assess the prognostic value of the ctDNA level. Plasma samples at diagnosis were available for 34 patients registered in the PRIMA trial (NCT00140582). One tumour clonotype or more could be detected for 29 (85%) and 25 (74%) patients, respectively, in the tumour or plasma samples. In 18 patients, several subclones were detected in the tumour (2 to 71 subclones/cases) and/or in the plasma (2 to 20 subclones/cases). In more than half of the cases, the distribution of subclones differed between the tumour and plasma samples, reflecting high clonal heterogeneity and diversity in lymphoma subclone dissemination. In multivariate analysis, a high level of ctDNA was the only independent factor associated with patients’ progression-free survival (HR 4, IC 95 (1.1-37), p=.039). In conclusion, an NGS-based immunosequencing method reveals the marked clonal heterogeneity of follicular lymphoma in patients with FL, and quantification of ctDNA at diagnosis represents a potential powerful prognostic biomarker that needs to be investigated in larger cohorts. PMID:28060738

  5. Clonal distribution of pneumococcal serotype 19F isolates from Ghana. (United States)

    Sparding, Nadja; Dayie, Nicholas T K D; Mills, Richael O; Newman, Mercy J; Dalsgaard, Anders; Frimodt-Møller, Niels; Slotved, Hans-Christian


    Streptococcus pneumoniae is a major cause of morbidity and mortality worldwide. Pneumococcal strains are classified according to their capsular polysaccharide and more than 90 different serotypes are currently known. In this project, three distinct groups of pneumococcal carriage isolates from Ghana were investigated; isolates from healthy children in Tamale and isolates from both healthy and children attending the outpatient department at a hospital in Accra. The isolates were previously identified and characterized by Gram staining, serotyping and susceptibility to penicillin. In this study, isolates of the common serotype 19F were further investigated by Multi-Locus Sequence Typing (MLST). Overall, 14 different Sequence Types (STs) were identified by MLST, of which nine were novel based on the international MLST database. Two clones within serotype 19F seem to circulate in Ghana, a known ST (ST 4194) and a novel ST (ST 9090). ST 9090 was only found in healthy children in Accra, whereas ST 4194 was found equally in all children studied. In the MLST database, other isolates of ST 4194 were also associated with serotype 19F, and these isolates came from other West African countries. The majority of isolates were penicillin intermediate resistant. In conclusion, two clones within serotype 19F were found to be dominating in pneumococcal carriage in Accra and Tamale in Ghana. Furthermore, it seems as though the clonal distribution of serotype 19F may be different from what is currently known in Ghana in that many new clones were identified. This supports the importance of continued monitoring of pneumococcal carriage in Ghana and elsewhere when vaccines, e.g., PCV-13, have been introduced to monitor the possible future spread of antimicrobial resistant clones.

  6. Clonal propagation of Bambusa vulgaris by leafy branch cuttings

    Institute of Scientific and Technical Information of China (English)

    M.S.Islam; M.K.Bhuiyan; M.M.Hossain; M.A.Hossain


    Bambusa vulgaris Schrad ex wendl is a widely cultivated bamboo species in rural Bangladesh for its versatile uses. The vegetative propagation becomes the only viable alternative for this species because B. vulgaris does not set seed after sparse flowering, which makes seed- ling progenies unavailable. A low-cost propagation trial was conducted to explore the clonal propagation techniques for the species with two types of small branch cuttings, nodal leafy cuttings and tip cuttings. The cuttings, after treating with 0, 0.1%, 0.4%, and 0.8% IBA solutions, were kept in non-mist propagator to let them to root for assessing the rooting ability. The cuttings were rooted in four weeks and were allowed to grow in the polybags for 10 months under nursery condition to assess their steckling capacity. The study reveals that both types of branch cuttings are able to develop roots, shoots, to survive and to form rhizome under the nursery condition. Rooting ability of the cuttings was significantly enhanced by the application of rooting hormone - IBA. The highest root- ing percentage in nodal leafy cuttings and the tip cuttings (56.67% and 51.0%, respectively) were observed in 0.8% IBA treatment, followed by 0.4% IBA and the lowest (34.3% and 30.0%, respectively) was in control. The highest number of root developed per cutting (9.77 and 8.33 in nodal leafy cuttings and the tip cuttings, respectively) was also obtained from the cuttings treated with 0.8% IBA solution, followed 0.4% IBA treat- ment and the lowest (3.1 and 2.1, respectively) was in the cuttings with- out treatment. However, the length of the longest root varied significantly neither with the cutting types nor the concentrations of IBA solution. Survival percentage of the stecklings in nursery condition was signifi- cantly enhanced by IBA.

  7. Burkholderia pseudomallei virulence: definition, stability and association with clonality. (United States)

    Ulett, G C; Currie, B J; Clair, T W; Mayo, M; Ketheesan, N; Labrooy, J; Gal, D; Norton, R; Smith, C A; Barnes, J; Warner, J; Hirst, R G


    Clinical presentations of melioidosis, caused by Burkholderia pseudomallei are protean, but the mechanisms underlying development of the different forms of disease remain poorly understood. In murine melioidosis, the level of virulence of B. pseudomallei is important in disease pathogenesis and progression. In this study, we used B. pseudomallei-susceptible BALB/c mice to determine the virulence of a library of clinical and environmental B. pseudomallei isolates from Australia and Papua New Guinea. Among 42 non-arabinose-assimilating (ara(-)) isolates, LD(50) ranged from 10 to > 10(6) CFU. There were numerous correlations between virulence and disease presentation in patients; however, this was not a consistent observation. Virulence did not correlate with isolate origin (i.e. clinical vs environmental), since numerous ara(-) environmental isolates were highly virulent. The least virulent isolate was a soil isolate from Papua New Guinea, which was arabinose assimilating (ara(+)). Stability of B. pseudomallei virulence was investigated by in vivo passage of isolates through mice and repetitive in vitro subculture. Virulence increased following in vivo exposure in only one of eight isolates tested. In vitro subculture on ferric citrate-containing medium caused attenuation of virulence, and this correlated with changes in colony morphology. Pulsed-field gel electrophoresis and randomly amplified polymorphic DNA typing demonstrated that selected epidemiologically related isolates that had variable clinical outcomes and different in vivo virulence were clonal strains. No molecular changes were observed in isolates after in vivo or in vitro exposure despite changes in virulence. These results indicate that virulence of selected B. pseudomallei isolates is variable, being dependent on factors such as iron bioavailability. They also support the importance of other variables such as inoculum size and host risk factors in determining the clinical severity of melioidosis.

  8. CpG oligodeoxynucleotides induce strong up-regulation of interleukin 33 via Toll-like receptor 9. (United States)

    Shimosato, Takeshi; Fujimoto, Megumi; Tohno, Masanori; Sato, Takashi; Tateo, Mariko; Otani, Hajime; Kitazawa, Haruki


    We previously reported the strong immunostimulatory effects of a CpG oligodeoxynucleotide (ODN), designated MsST, from the lacZ gene of Streptococcus (S.) thermophilus ATCC19258. Here we show that 24h of stimulation with MsST in mouse splenocytes and peritoneal macrophages strongly induces expression of interleukin (IL)-33, a cytokine in the IL-1 superfamily. Other IL-1 superfamily members, including IL-1alpha, IL-1beta and IL-18, are down-regulated after 24h of stimulation of MsST. We also found that MsST-induced IL-33 mRNA expression is inhibited by the suppressive ODN A151, which can inhibit Toll-like receptor 9 (TLR9)-mediated responses. This is the first report to show that IL-33 can be induced by CpG ODNs. The strong induction of IL-33 by MsST suggests that it may be a potential therapeutic ODN for the treatment of inflammatory disease. The presence of a strong CpG ODN in S. thermophilus also suggests that the bacterium may be a good candidate as a starter culture for the development of new physiologically functional foods.

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

    Directory of Open Access Journals (Sweden)

    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.

  10. Cationic liposomes containing soluble Leishmania antigens (SLA) plus CpG ODNs induce protection against murine model of leishmaniasis. (United States)

    Heravi Shargh, Vahid; Jaafari, Mahmoud Reza; Khamesipour, Ali; Jalali, Seyed Amir; Firouzmand, Hengameh; Abbasi, Azam; Badiee, Ali


    Development of an effective vaccine against leishmaniasis is possible due to the fact that individuals cured from cutaneous leishmaniasis (CL) are protected from further infection. First generation Leishmania vaccines consisting of whole killed parasites reached to phase 3 clinical trials but failed to show enough efficacies mainly due to the lack of an appropriate adjuvant. In this study, an efficient liposomal protein-based vaccine against Leishmania major infection was developed using soluble Leishmania antigens (SLA) as a first generation vaccine and cytidine phosphate guanosine oligodeoxynucleotides (CpG ODNs) as an immunostimulatory adjuvant. 1, 2-Dioleoyl-3-trimethylammonium-propane was used as a cationic lipid to prepare the liposomes due to its intrinsic adjuvanticity. BALB/c mice were immunized subcutaneously (SC), three times in 2-week intervals, with Lip-SLA-CpG, Lip-SLA, SLA + CpG, SLA, or HEPES buffer. As criteria for protection, footpad swelling at the site of challenge and spleen parasite loads were assessed, and the immune responses were evaluated by determination of IFN-γ and IL-4 levels of cultured splenocytes, and IgG subtypes. The group of mice that received Lip-SLA-CpG showed a significantly smaller footpad swelling, lower spleen parasite burden, higher IgG2a antibody, and lower IL-4 level compared to the control groups. It is concluded that cationic liposomes containing SLA and CpG ODNs are appropriate to induce Th1 type of immune response and protection against leishmaniasis.

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

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    Qiao Yingjuan


    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.

  12. A Panel of CpG Methylation Sites Distinguishes Human Embryonic Stem Cells and Induced Pluripotent Stem Cells

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    Kevin Huang


    Full Text Available Whether human induced pluripotent stem cells (hiPSCs are epigenetically identical to human embryonic stem cells (hESCs has been debated in the stem cell field. In this study, we analyzed DNA methylation patterns in a large number of hiPSCs (n = 114 and hESCs (n = 155, and identified a panel of 82 CpG methylation sites that can distinguish hiPSCs from hESCs with high accuracy. We show that 12 out of the 82 CpG sites were subject to hypermethylation in part by DNMT3B. Notably, DNMT3B contributes directly to aberrant hypermethylation and silencing of the signature gene, TCERG1L. Overall, we conclude that DNMT3B is involved in a wave of de novo methylation during reprogramming, a portion of which contributes to the unique hiPSC methylation signature. These 82 CpG methylation sites may be useful as biomarkers to distinguish between hiPSCs and hESCs.

  13. PRIMEGENS-v2: genome-wide primer design for analyzing DNA methylation patterns of CpG islands. (United States)

    Srivastava, Gyan P; Guo, Juyuan; Shi, Huidong; Xu, Dong


    DNA methylation plays important roles in biological processes and human diseases, especially cancers. High-throughput bisulfite genomic sequencing based on new generation of sequencers, such as the 454-sequencing system provides an efficient method for analyzing DNA methylation patterns. The successful implementation of this approach depends on the use of primer design software capable of performing genome-wide scan for optimal primers from in silico bisulfite-treated genome sequences. We have developed a method, which fulfills this requirement and conduct primer design for sequences including regions of given promoter CpG islands. The developed method has been implemented using the C and JAVA programming languages. The primer design results were tested in the PCR experiments of 96 selected human DNA sequences containing CpG islands in the promoter regions. The results indicate that this method is efficient and reliable for designing sequence-specific primers. The sequence-specific primer design for DNA meth-ylated sequences including CpG islands has been integrated into the second version of PRIMEGENS as one of the primer design features. The software is freely available for academic use at

  14. 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

    Full Text Available BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION/SIGNIFICANCE: 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. TRIAL REGISTRATION: NCT00344539.

  15. Methylation-Specific MLPA (MS-MLPA): simultaneous detection of CpG methylation and copy number changes of up to 40 sequences


    Nygren, Anders O.H.; Ameziane, Najim; Duarte, Helena M. B.; Vijzelaar, Raymon N. C. P.; Waisfisz, Quinten; Hess, Corine J.; Jan. P. Schouten; Errami, Abdellatif


    Copy number changes and CpG methylation of various genes are hallmarks of tumor development but are not yet widely used in diagnostic settings. The recently developed multiplex ligation-dependent probe amplification (MLPA) method has increased the possibilities for multiplex detection of gene copy number aberrations in a routine laboratory. Here we describe a novel robust method: the methylation-specific MLPA (MS-MLPA) that can detect changes in both CpG methylation as well as copy number of ...

  16. Enhanced antibody responses elicited by a CpG adjuvant do not improve the protective effect of an aldrithiol-2-inactivated simian immunodeficiency virus therapeutic AIDS vaccine. (United States)

    Wang, Yichuan; Blozis, Shelley A; Lederman, Michael; Krieg, Arthur; Landay, Alan; Miller, Christopher J


    The potential benefit of using unmethylated CpG oligoribodeoxynucleotides (ODN) as an adjuvant in a therapeutic simian immunodeficiency virus (SIV) vaccine consisting of AT2-inactivated SIVmac239 was evaluated in SIV-infected rhesus macaques receiving antiretroviral therapy (ART). We hypothesized that using CpG ODN as an adjuvant in therapeutic vaccination would enhance SIV-specific immune responses and suppress SIV replication after ART was stopped. To test our hypothesis, we immunized chronically SIV-infected rhesus macaques receiving ART with one of the following therapeutic vaccines: (i) AT2-inactivated SIVmac239, (ii) CpG10103 plus AT2-inactivated SIVmac239, (iii) CpG10103, and (iv) saline. While immunization with CpG plus AT2-SIVmac239 significantly increased SIV-specific immunoglobulin G (IgG) antibody titers, the mean plasma viral RNA (vRNA) level in these animals after ART did not differ from those of saline-treated animals. The AT2-inactivated SIVmac239-immunized animal group had a significantly higher mean SIV-specific gamma interferon T-cell response after three immunizations and lower plasma vRNA levels for 6 weeks after ART was withdrawn compared to the saline-treated animal group. Compared to the saline control group, the animal group treated with CpG alone had a significantly higher mean SIV-specific lymphocyte proliferation index and a higher rate of plasma vRNA rebound after ART. These results demonstrate that while the use of CpG as an adjuvant enhances SIV-specific antibody responses, this does not improve the control of SIV replication after ART is stopped. The lack of benefit may be related to the high levels of SIV-specific lymphocyte proliferation in the CpG adjuvant group.

  17. Mechanisms of Organelle Inheritance in Dividing Plant Cells

    Institute of Scientific and Technical Information of China (English)


    Organelles form essential compartments of all eukaryotic cells. Mechanisms that ensure the unbiased inheritance of organelles during cell division are therefore necessary to maintain the viability of future cell generations. Although inheritance of organelles represents a fundamental component of the cell cycle, surprisingly little is known about the underlying mechanisms that facilitate unbiased organelle inheritance. Evidence from a select number of studies, however,indicates that ordered organelle inheritance strategies exist in dividing cells of higher plants. The basic requirement for unbiased organelle inheritance is the duplication of organelle volume and distribution of the resulting organelle populations in a manner that facilitates unbiased partitioning of the organelle population to each daughter cell. Often, partitioning strategies are specific to the organelle, being influenced by the functional requirements of the organelle and whether the cells are mitotically active or re-entering into the cell cycle. Organelle partitioning mechanisms frequently depend on interactions with either the actin or microtubule cytoskeleton. In this focused review, we attempt to summarize key findings regarding organelle partitioning strategies in dividing cells of higher plants. We particularly concentrate on the role of the cytoskeleton in mediating unbiased organelle partitioning.

  18. Mitochondrial fusion and inheritance of the mitochondrial genome. (United States)

    Takano, Hiroyoshi; Onoue, Kenta; Kawano, Shigeyuki


    Although maternal or uniparental inheritance of mitochondrial genomes is a general rule, biparental inheritance is sometimes observed in protists and fungi,including yeasts. In yeast, recombination occurs between the mitochondrial genomes inherited from both parents.Mitochondrial fusion observed in yeast zygotes is thought to set up a space for DNA recombination. In the last decade,a universal mitochondrial fusion mechanism has been uncovered, using yeast as a model. On the other hand, an alternative mitochondrial fusion mechanism has been identified in the true slime mold Physarum polycephalum.A specific mitochondrial plasmid, mF, has been detected as the genetic material that causes mitochondrial fusion in P. polycephalum. Without mF, fusion of the mitochondria is not observed throughout the life cycle, suggesting that Physarum has no constitutive mitochondrial fusion mechanism.Conversely, mitochondria fuse in zygotes and during sporulation with mF. The complete mF sequence suggests that one gene, ORF640, encodes a fusogen for Physarum mitochondria. Although in general, mitochondria are inherited uniparentally, biparental inheritance occurs with specific sexual crossing in P. polycephalum.An analysis of the transmission of mitochondrial genomes has shown that recombinations between two parental mitochondrial genomes require mitochondrial fusion,mediated by mF. Physarum is a unique organism for studying mitochondrial fusion.

  19. Maternal telomere length inheritance in the king penguin. (United States)

    Reichert, S; Rojas, E R; Zahn, S; Robin, J-P; Criscuolo, F; Massemin, S


    Telomeres are emerging as a biomarker for ageing and survival, and are likely important in shaping life-history trade-offs. In particular, telomere length with which one starts in life has been linked to lifelong survival, suggesting that early telomere dynamics are somehow related to life-history trajectories. This result highlights the importance of determining the extent to which telomere length is inherited, as a crucial factor determining early life telomere length. Given the scarcity of species for which telomere length inheritance has been studied, it is pressing to assess the generality of telomere length inheritance patterns. Further, information on how this pattern changes over the course of growth in individuals living under natural conditions should provide some insight on the extent to which environmental constraints also shape telomere dynamics. To fill this gap partly, we followed telomere inheritance in a population of king penguins (Aptenodytes patagonicus). We tested for paternal and maternal influence on chick initial telomere length (10 days old after hatching), and how these relationships changed with chick age (at 70, 200 and 300 days old). Based on a correlative approach, offspring telomere length was positively associated with maternal telomere length early in life (at 10 days old). However, this relationship was not significant at older ages. These data suggest that telomere length in birds is maternally inherited. Nonetheless, the influence of environmental conditions during growth remained an important factor shaping telomere length, as the maternal link disappeared with chicks' age.

  20. Inheritance of hereditary equine regional dermal asthenia in Quarter Horses. (United States)

    Tryon, Robert C; White, Stephen D; Famula, Thomas R; Schultheiss, Patricia C; Hamar, Dwayne W; Bannasch, Danika L


    To assess heritability and mode of inheritance for hereditary equine regional dermal asthenia (HERDA) in Quarter Horses. 1,295 horses with Quarter Horse bloodlines, including 58 horses affected with HERDA. Horses were classified as affected or unaffected or as undetermined when data were insufficient to assess phenotype. Pedigree data were analyzed to determine the probable mode of inheritance. Heritability was estimated by use of Bayesian statistical methods. Heritability (mean+/-SD) of HERDA was estimated to be 0.38+/-0.13, with both sexes having an equal probability of being affected. Results for evaluation of the pedigrees were consistent with a single Mendelian autosomal recessive mode of inheritance. HERDA in Quarter Horses is an inherited disease, and affected horses are more likely to produce affected offspring. An autosomal recessive mode of inheritance should be considered by people making breeding decisions involving Quarter Horses when a first-degree relative has been confirmed with HERDA or has produced affected offspring. In addition, breeders whose horses have produced affected offspring can reduce the likelihood of producing affected horses in the future by avoiding inbreeding.

  1. Inherited Retinal Disease Therapies Targeting Precursor Messenger Ribonucleic Acid

    Directory of Open Access Journals (Sweden)

    Di Huang


    Full Text Available Inherited retinal diseases are an extremely diverse group of genetically and phenotypically heterogeneous conditions characterized by variable maturation of retinal development, impairment of photoreceptor cell function and gradual loss of photoreceptor cells and vision. Significant progress has been made over the last two decades in identifying the many genes implicated in inherited retinal diseases and developing novel therapies to address the underlying genetic defects. Approximately one-quarter of exonic mutations related to human inherited diseases are likely to induce aberrant splicing products, providing opportunities for the development of novel therapeutics that target splicing processes. The feasibility of antisense oligomer mediated splice intervention to treat inherited diseases has been demonstrated in vitro, in vivo and in clinical trials. In this review, we will discuss therapeutic approaches to treat inherited retinal disease, including strategies to correct splicing and modify exon selection at the level of pre-mRNA. The challenges of clinical translation of this class of emerging therapeutics will also be discussed.

  2. Tissue specific DNA methylation of CpG islands in normal human adult somatic tissues distinguishes neural from non-neural tissues. (United States)

    Ghosh, Srimoyee; Yates, Allan J; Frühwald, Michael C; Miecznikowski, Jeffrey C; Plass, Christoph; Smiraglia, Dominic


    Although most CpG islands are generally thought to remain unmethylated in all adult somatic tissues, recent genome-wide approaches have found that some CpG islands have distinct methylation patterns in various tissues, with most differences being seen between germ cells and somatic tissues. Few studies have addressed this among human somatic tissues and fewer still have studied the same sets of tissues from multiple individuals. In the current study, we used Restriction Landmark Genomic Scanning to study tissue specific methylation patterns in a set of twelve human tissues collected from multiple individuals. We identified 34 differentially methylated CpG islands among these tissues, many of which showed consistent patterns in multiple individuals. Of particular interest were striking differences in CpG island methylation, not only among brain regions, but also between white and grey matter of the same region. These findings were confirmed for selected loci by quantitative bisulfite sequencing. Cluster analysis of the RLGS data indicated that several tissues clustered together, but the strongest clustering was in brain. Tissues from different brain regions clustered together, and, as a group, brain tissues were distinct from either mesoderm or endoderm derived tissues which demonstrated limited clustering. These data demonstrate consistent tissue specific methylation for certain CpG islands, with clear differences between white and grey matter of the brain. Furthermore, there was an overall pattern of tissue specifically methylated CpG islands that distinguished neural tissues from non-neural.

  3. CpG oligodeoxynucleotides augment the murine immune response to the Yersinia pestis F1-V vaccine in bubonic and pneumonic models of plague. (United States)

    Amemiya, Kei; Meyers, Jennifer L; Rogers, Taralyn E; Fast, Randy L; Bassett, Anthony D; Worsham, Patricia L; Powell, Bradford S; Norris, Sarah L; Krieg, Arthur M; Adamovicz, Jeffrey J


    The current U.S. Department of Defense candidate plague vaccine is a fusion between two Yersinia pestis proteins: the F1 capsular protein, and the low calcium response (Lcr) V-protein. We hypothesized that an immunomodulator, such as CpG oligodeoxynucleotide (ODN)s, could augment the immune response to the plague F1-V vaccine in a mouse model for plague. CpG ODNs significantly augmented the antibody response and efficacy of a single dose of the plague vaccine in murine bubonic and pneumonic models of plague. In the latter study, we also found an overall significant augmentation the immune response to the individual subunits of the plague vaccine by CpG ODN 2006. In a long-term, prime-boost study, CpG ODN induced a significant early augmentation of the IgG response to the vaccine. The presence of CpG ODN induced a significant increase in the IgG2a subclass response to the vaccine up to 5 months after the boost. Our studies showed that CpG ODNs significantly augmented the IgG antibody response to the plague vaccine, which increased the probability of survival in murine models of plague (P<0.0001).

  4. Transcriptomic Insights into the Response of Placenta and Decidua Basalis to the CpG Oligodeoxynucleotide Stimulation in Non-Obese Diabetic Mice and Wild-Type Controls

    Directory of Open Access Journals (Sweden)

    Xiao-Rui Liu


    Full Text Available Intrauterine infection is one of the most frequent causes of miscarriage. CpG oligodeoxynucleotide (CpG ODN can mimic intrauterine infection. CpG ODN-induced embryo-resorption was observed consistently in the NK-cell deficient non-obese diabetic (NOD mice but not in the wild-type (WT mice. To elucidate the molecular mechanisms of differential pregnancy outcomes, differentially expressed genes (DEGs in the placenta and decidua basalis was revealed by RNA-Seq with CpG ODN or control ODN treatment. Common DEGs in the WT and NOD mice were enriched in antimicrobial/antibacterial humoral responses that may be activated as a primary response to bacterial infection. The susceptibility to CpG ODN-induced embryo-resorption in the NOD mice might mainly be attributed to M1 macrophage polarization and the immunodeficient status, such as the down-regulation in antigen processing and presentation, allograft rejection, and natural killer cell mediated cytotoxicity. In contrast, the WT mice with normal immune systems could activate multiple immune responses and be resistant to CpG ODN-induced embryo-resorption, such as M2 macrophage differentiation and activation regulated by complement component C1q and peroxisome proliferation-activated receptor (PPAR signaling pathways. Collectively, this study suggests that the immunodeficient status of NOD mice and the macrophage polarization regulated by C1q and PPAR signaling might be the basis for differential pregnancy outcomes between the NOD and WT mice.

  5. Quantitative, high-resolution epigenetic profiling of CpG loci identifies associations with cord blood plasma homocysteine and birth weight in humans. (United States)

    Fryer, Anthony A; Emes, Richard D; Ismail, Khaled M K; Haworth, Kim E; Mein, Charles; Carroll, William D; Farrell, William E


    Supplementation with folic acid during pregnancy is known to reduce the risk of neural tube defects and low birth weight. It is thought that folate and other one-carbon intermediates might secure these clinical effects via DNA methylation. We examined the effects of folate on the human methylome using quantitative interrogation of 27,578 CpG loci associated with 14,496 genes at single-nucleotide resolution across 12 fetal cord blood samples. Consistent with previous studies, the majority of CpG dinucleotides located within CpG islands exhibited hypo-methylation while those outside CpG islands showed mid-high methylation. However, for the first time in human samples, unbiased analysis of methylation across samples revealed a significant correlation of methylation patterns with plasma homocysteine, LINE-1 methylation and birth weight centile. Additionally, CpG methylation significantly correlated with either birth weight or LINE-1 methylation were predominantly located in CpG islands. These data indicate that levels of folate-associated intermediates in cord blood reflect their influence and consequences for the fetal epigenome and potentially on pregnancy outcome. In these cases, their influence might be exerted during late gestation or reflect those present during the peri-conceptual period.

  6. Organosilane and Polyethylene Glycol Functionalized Magnetic Mesoporous Silica Nanoparticles as Carriers for CpG Immunotherapy In Vitro and In Vivo.

    Directory of Open Access Journals (Sweden)

    Hengrui Zheng

    Full Text Available Cytosine-guanine (CpG containing oligodeoxynucleotides (ODN have significant clinical potential as immunotherapeutics. However, limitations exist due to their transient biological stability in vivo, lack of specificity for target cells, and poor cellular uptake. To address these issues, we prepared amine magnetic mesoporous silica nanoparticles (M-MSN-A then further modified with polyethylene glycol (PEG for use as CpG delivery vectors. The PEG modified M-MSN-A (M-MSN-P had notable CpG ODN loading capacity, negligible cytotoxicity, and were easily internalized into cells where they released the loaded CpG into the cytoplasm. As a result, such complexes were effective in activating macrophages and inhibiting tumor cells when combined with chemotherapeutics in vitro. Furthermore, these complexes had excellent immuno-stimulating activity in vivo, compared to the free CpG therapeutics. We report here a highly effective MSNs-based delivery system with great potential as a therapeutic CpG formulation in cancer immunotherapy.

  7. 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))


    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.


    Johannesson, Kerstin; Johansson, Daniel; Larsson, Karl H; Huenchuñir, Cecilia J; Perus, Jens; Forslund, Helena; Kautsky, Lena; Pereyra, Ricardo T


    Asexual reproduction by cloning may affect the genetic structure of populations, their potential to evolve, and, among foundation species, contributions to ecosystem functions. Macroalgae of the genus Fucus are known to produce attached plants only by sexual recruitment. Recently, however, clones of attached plants recruited by asexual reproduction were observed in a few populations of Fucus radicans Bergström et L. Kautsky and F. vesiculosus L. inside the Baltic Sea. Herein we assess the distribution and prevalence of clonality in Baltic fucoids using nine polymorphic microsatellite loci and samples of F. radicans and F. vesiculosus from 13 Baltic sites. Clonality was more common in F. radicans than in F. vesiculosus, and in both species it tended to be most common in northern Baltic sites, although variation among close populations was sometimes extensive. Individual clonal lineages were mostly restricted to single or nearby locations, but one clonal lineage of F. radicans dominated five of 10 populations and was widely distributed over 550 × 100 km of coast. Populations dominated by a few clonal lineages were common in F. radicans, and these were less genetically variable than in other populations. As thalli recruited by cloning produced gametes, a possible explanation for this reduced genetic variation is that dominance of one or a few clonal lineages biases the gamete pool resulting in a decreased effective population size and thereby loss of genetic variation by genetic drift. Baltic fucoids are important habitat-forming species, and genetic structure and presence of clonality have implications for conservation strategies.

  9. Clonal analysis and virulent traits of pathogenic extraintestinal Escherichia coli isolates from swine in China

    Directory of Open Access Journals (Sweden)

    Ding Yi


    Full Text Available Abstract Background Extraintestinal pathogenic Escherichia coli (ExPEC can cause a variety of infections outside the gastrointestinal tract in humans and animals. Infections due to swine ExPECs have been occurring with increasing frequency in China. These ExPECs may now be considered a new food-borne pathogen that causes cross-infections between humans and pigs. Knowledge of the clonal structure and virulence genes is needed as a framework to improve the understanding of phylogenetic traits of porcine ExPECs. Results Multilocus sequence typing (MLST data showed that the isolates investigated in this study could be placed into four main clonal complexes, designated as CC10, CC1687, CC88 and CC58. Strains within CC10 were classified as phylogroup A, and these accounted for most of our porcine ExPEC isolates. Isolates in the CC1687 clonal complex, formed by new sequence types (STs, was classified as phylogroup D, with CC88 isolates considered as B2 and CC58 isolates as B1. Porcine ExPECs in these four clonal complexes demonstrated significantly different virulence gene patterns. A few porcine ExPECs were indentified in phylogroup B2, the phylogroup in which human ExPECs mainly exist. However some STs in the four clonal groups of porcine ExPECs were reported to cause extraintestinal infections in human, based on data in the MLST database. Conclusion Porcine ExPECs have different virulence gene patterns for different clonal complexes. However, these strains are mostly fell in phylogenentic phylogroup A, B1 and D, which is different from human ExPECs that concentrate in phylogroup B2. Our findings provide a better understanding relating to the clonal structure of ExPECs in diseased pigs and indicate a need to re-evaluate their contribution to human ExPEC diseases.

  10. Phylogenetic meta-analysis of the functional traits of clonal plants foraging in changing environments. (United States)

    Xie, Xiu-Fang; Song, Yao-Bin; Zhang, Ya-Lin; Pan, Xu; Dong, Ming


    Foraging behavior, one of the adaptive strategies of clonal plants, has stimulated a tremendous amount of research. However, it is a matter of debate whether there is any general pattern in the foraging traits (functional traits related to foraging behavior) of clonal plants in response to diverse environments. We collected data from 97 published papers concerning the relationships between foraging traits (e.g., spacer length, specific spacer length, branch intensity and branch angle) of clonal plants and essential resources (e.g., light, nutrients and water) for plant growth and reproduction. We incorporated the phylogenetic information of 85 plant species to examine the universality of foraging hypotheses using phylogenetic meta-analysis. The trends toward forming longer spacers and fewer branches in shaded environments were detected in clonal plants, but no evidence for a relation between foraging traits and nutrient availability was detected, except that there was a positive correlation between branch intensity and nutrient availability in stoloniferous plants. The response of the foraging traits of clonal plants to water availability was also not obvious. Additionally, our results indicated that the foraging traits of stoloniferous plants were more sensitive to resource availability than those of rhizomatous plants. In consideration of plant phylogeny, these results implied that the foraging traits of clonal plants (notably stoloniferous plants) only responded to light intensity in a general pattern but did not respond to nutrient or water availability. In conclusion, our findings on the effects of the environment on the foraging traits of clonal plants avoided the confounding effects of phylogeny because we incorporated phylogeny into the meta-analysis.

  11. Importancia de la integración clonal en las invasiones biológicas

    Directory of Open Access Journals (Sweden)

    S.R. Roiloa


    Full Text Available Un aspecto clave en el estudio de las invasiones biológicas es el de explicar por qué algunas especies se convierten en invasoras mientras que otras no. A pesar de los esfuerzos realizados durante los últimos años los mecanismos subyacentes en los procesos de invasiones biológicas todavía no están completamente desentrañados. Algunas características de las plantas pueden explicar mejor que otras el éxito de algunas especies invasoras. El crecimiento clonal ha sido señalado como un atributo que podría contribuir a la capacidad invasora de las plantas. Sin embargo, y a pesar de que muchas de las especies vegetales más agresivas son clonales, pocos trabajos se han dirigido a determinar el papel de la clonalidad en las invasiones biológicas. Las plantas clonales juegan un papel clave en los ecosistemas y dominan muchas comunidades vegetales. Uno de los atributos más interesantes asociados al crecimiento clonal y que podría explicar su éxito es la capacidad de integración fisiológica (intercambio de recursos entre los individuos del clon. Estudios recientes han demostrado cómo la integración clonal favorece la supervivencia y el crecimiento en especies vegetales que poseen una alta capacidad invasora. Sin embargo, futuros estudios comparando la capacidad de integración clonal entre congéneres exóticos no-invasores e invasores y entre poblaciones de rango nativo e invadido, son necesarias para determinar la presencia de evolución adaptativa en atributos asociados al crecimiento clonal durante el proceso de invasión y así establecer el papel de la clonalidad en las invasiones biológicas.

  12. PCR-based clonality assessment in patients with lymphocytic leukaemias: a single-institution experience

    Indian Academy of Sciences (India)

    Bojana M. Cikota; Ljiljana J. Tukić; Olivera T. Tarabar; Dragana T. Stamatović; Marija N. Elez; Zvonko M. Magić


    PCR-based clonality testing can be performed in all lymphoproliferations by analysing gene rearrangements of antigen receptors, rearrangements that are unique for each kind of lymphocyte. Reactive lymphoproliferations have polyclonally rearranged Ig/TCR genes, whereas malignant proliferations (leukaemias and lymphomas) show clonal rearrangements. The aim of this study was to assess the clinical benefits of clonality testing with previously evaluated consensus primers in leukaemia patients. The study included peripheral blood and bone marrow samples of 67 leukaemia patients (32 B-CLL, 24 B-ALL and 11 T-ALL). Clonality testing was based on PCR amplification of rearranged I$_{\\text{gH}}$ and TCR genes. During diagnosis, monoclonal pattern was found in all analysed B-CLL and T-ALL samples. Testing in B-ALL patients showed positive results in all bone marrow and one peripheral blood samples. Results of clonality testing in B-CLL patients during follow-up were concordant between peripheral blood and bone marrow. Obtained results corresponded to clinical course in all but one patient. In B-ALL group, results of molecular testing in peripheral blood and bone marrow confirmed remission estimated according to clinical criteria in all except one patient. Before any clinical sign of relapse, monoclonal pattern was found in six/seven patients by bone marrow and in three/seven patients by peripheral blood analysis, respectively. Results of molecular monitoring in T-ALL patients did not confirme clinical evaluation in two patients. Obtained results indicate high accuracy of re-evaluated primers for clonality assessment in ALL and CLL patients at the time of diagnosis. Results of clonality testing in B-ALL patients indicate that bone marrow analysis has higher sensitivity compared to analysis of peripheral blood.

  13. Assessment of various strategies for the preservation of clonal genetic resources in oil palm (Elaeis guineensis Jacq.)


    Konan, K.E.; Rival, A.; Kouadio, Y. J.; Duval, Yves; Flori, A.; Adon, B.; Pene, C.; Gasselin, T.D.


    Three different approaches for the preservation of oil palm (Elaeis guineensis Jacq.) clonal genetic resources and their impacts on the induction of the « mantled » somaclonal variation were assessed. In vitro long term preservation of somatic embryos stock-cultures was studied : after a 5 year cultivation period, 75 % of clonal lines were still normal. Between 8 and 13 years of embryo cultures, half of the considered clonal lines were found to be « mantled ». Finally, 40 % were found t...

  14. Theoretical Validation of Inheritance Metrics for Object-Oriented Design against Briand's Property

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    Kumar Rajnish


    Full Text Available Many inheritance metrics can be found in the literature, but most of those are validated theoretically by using Weyuker's property. Theoretical validation of inheritance metrics using Briand's property is rare in the literature. This paper considers the metrics proposed by Rajnish and Sandip and presents a theoretical validation of the inheritance metrics using the Briand's size and length properties of an inheritance hierarchy. This paper also gives the projection and viewpoint of the inheritance metrics.

  15. Genome-Wide Locations of Potential Epimutations Associated with Environmentally Induced Epigenetic Transgenerational Inheritance of Disease Using a Sequential Machine Learning Prediction Approach. (United States)

    Haque, M Muksitul; Holder, Lawrence B; Skinner, Michael K


    Environmentally induced epigenetic transgenerational inheritance of disease and phenotypic variation involves germline transmitted epimutations. The primary epimutations identified involve altered differential DNA methylation regions (DMRs). Different environmental toxicants have been shown to promote exposure (i.e., toxicant) specific signatures of germline epimutations. Analysis of genomic features associated with these epimutations identified low-density CpG regions (learning computational approach to predict all potential epimutations in the genome. A number of previously identified sperm epimutations were used as training sets. A novel machine learning approach using a sequential combination of Active Learning and Imbalance Class Learner analysis was developed. The transgenerational sperm epimutation analysis identified approximately 50K individual sites with a 1 kb mean size and 3,233 regions that had a minimum of three adjacent sites with a mean size of 3.5 kb. A select number of the most relevant genomic features were identified with the low density CpG deserts being a critical genomic feature of the features selected. A similar independent analysis with transgenerational somatic cell epimutation training sets identified a smaller number of 1,503 regions of genome-wide predicted sites and differences in genomic feature contributions. The predicted genome-wide germline (sperm) epimutations were found to be distinct from the predicted somatic cell epimutations. Validation of the genome-wide germline predicted sites used two recently identified transgenerational sperm epimutation signature sets from the pesticides dichlorodiphenyltrichloroethane (DDT) and methoxychlor (MXC) exposure lineage F3 generation. Analysis of this positive validation data set showed a 100% prediction accuracy for all the DDT-MXC sperm epimutations. Observations further elucidate the genomic features associated with transgenerational germline epimutations and identify a genome-wide set

  16. Using Types and Inheritance in Object-Oriented Languages (United States)

    Halbert, Daniel C.; O'Brien, Patrick D.

    If the object-oriented style of programming hopes to live up to its potential as an improved methodology for software programming, a clear understanding of how to use types and inheritance is essential. Our experiences with using object-oriented languages and teaching object-oriented techniques to other programmers have shown that effective use of types and inheritance may be problematic. There are no concrete guidelines to assist programmers, and the existing aphorisms often create interpretation problems for novice object-oriented programmers. In this paper we look at how types, subtyping, and inheritance are used in object-oriented languages. We discuss the different ways that types and type hierarchies can be used to structure programs. We illustrate appropriate use of these concepts through examples and develop guidelines to assist programmers in using the object-oriented methodology effectively.

  17. Inheriting the past: Exploring historical consciousness across generations

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    Anna Clark


    Full Text Available Despite significant research into the meaning and operation of historical consciousness, there is still much to be understood about its hereditary function. For example, what does historical inheritance look like? How does it influence our individual and collective historical consciousnesses? And, just as critically, what happens to historical consciousness when history is deliberately withheld, when that inheritance is suspended or severed? As a way into some of these questions about passing on the past, this paper draws on a qualitative research project into historical consciousness in Australia to explore how so-called ‘ordinary people’ see themselves as part of a historical narrative. It reveals that historical inheritance is critical to our historical consciousness, and it notes the profound impact of forgetting on participants, raising important questions about the role of ‘silence’ and ‘absence’ in the formation of historical consciousness.

  18. Cancer resistance as an acquired and inheritable trait

    DEFF Research Database (Denmark)

    Koch, Janne; Hau, Jann; Jensen, Henrik Elvang


    AIM: To induce cancer resistance in wild-type mice and detect if the resistance could be inherited to the progeny of the induced resistant mice. Furthermore to investigate the spectrum and immunology of this inherited cancer resistance. MATERIALS AND METHODS: Resistance to with live S180 cancer...... cells in BALB/c mice was induced by immunization with inactivated S180 cancer cells. The immunization was performed by either frozen/thawed or irradiated cancer cells or cell-free ascitic fluid (CFAF). RESULTS: In all instances the induced resistance was demonstrated to be inheritable. The phenotype...... was named HICR (heritable induced cancer resistance) and was defined as primary resistant progeny from mice immunized with frozen/thawed or irradiated S180 cells or CFAF obtained from mice with S180 induced ascites. Notably, this resistance was transferred from both male and female mice to the offspring...

  19. Linking DNA replication to heterochromatin silencing and epigenetic inheritance

    Institute of Scientific and Technical Information of China (English)

    Qing Li; Zhiguo Zhang


    Chromatin is organized into distinct functional domains.During mitotic cell division,both genetic information encoded in DNA sequence and epigenetic information embedded in chromatin structure must be faithfully duplicated.The inheritance of epigenetic states is critical in maintaining the genome integrity and gene expression state.In this review,we will discuss recent progress on how proteins known to be involved in DNA replication and DNA replication-coupled nucleosome assembly impact on the inheritance and maintenance of heterochromatin,a tightly compact chromatin structure that silences gene transcription.As heterochromatin is important in regulating gene expression and maintaining genome stability,understanding how heterochromatin states are inherited during S phase of the cell cycle is of fundamental importance.

  20. Ancient origin and maternal inheritance of blue cuckoo eggs. (United States)

    Fossøy, Frode; Sorenson, Michael D; Liang, Wei; Ekrem, Torbjørn; Moksnes, Arne; Møller, Anders P; Rutila, Jarkko; Røskaft, Eivin; Takasu, Fugo; Yang, Canchao; Stokke, Bård G


    Maternal inheritance via the female-specific W chromosome was long ago proposed as a potential solution to the evolutionary enigma of co-existing host-specific races (or 'gentes') in avian brood parasites. Here we report the first unambiguous evidence for maternal inheritance of egg colouration in the brood-parasitic common cuckoo Cuculus canorus. Females laying blue eggs belong to an ancient (∼2.6 Myr) maternal lineage, as evidenced by both mitochondrial and W-linked DNA, but are indistinguishable at nuclear DNA from other common cuckoos. Hence, cuckoo host races with blue eggs are distinguished only by maternally inherited components of the genome, which maintain host-specific adaptation despite interbreeding among males and females reared by different hosts. A mitochondrial phylogeny suggests that blue eggs originated in Asia and then expanded westwards as female cuckoos laying blue eggs interbred with the existing European population, introducing an adaptive trait that expanded the range of potential hosts.

  1. Inherited disorders of hemostasis in dogs and cats. (United States)

    Barr, James W; McMichael, Maureen


    Inherited disorders of hemostasis encompass abnormalities in primary hemostasis, coagulation, and fibrinolysis resulting from genetic mutations. There is significant variation in the phenotype expressed ranging from life limiting to the absence of overt clinical signs. Von Willebrand disease is the most common primary hemostatic disorder in dogs, and hemophilia A is the most common coagulation factor disorder. The diagnosis of inherited bleeding disorders is made by functional and/or quantitative evaluation. Genetic testing has added to the knowledge base, allowing prevention through targeted breeding. Avoidance of trauma and injury is paramount in the prevention of bleeding in animals diagnosed with inherited hemostatic disorders. Current therapeutic options include platelet transfusions, broad replacement of coagulation factors (e.g., plasma), targeted factor replacement (e.g., cryoprecipitate), antifibrinolytic agents and specific factor replacement, and treatment of the symptoms (i.e., bleeding) with blood transfusions.

  2. Rare inherited kidney diseases: challenges, opportunities, and perspectives. (United States)

    Devuyst, Olivier; Knoers, Nine V A M; Remuzzi, Giuseppe; Schaefer, Franz


    At least 10% of adults and nearly all children who receive renal-replacement therapy have an inherited kidney disease. These patients rarely die when their disease progresses and can remain alive for many years because of advances in organ-replacement therapy. However, these disorders substantially decrease their quality of life and have a large effect on health-care systems. Since the kidneys regulate essential homoeostatic processes, inherited kidney disorders have multisystem complications, which add to the usual challenges for rare disorders. In this review, we discuss the nature of rare inherited kidney diseases, the challenges they pose, and opportunities from technological advances, which are well suited to target the kidney. Mechanistic insights from rare disorders are relevant for common disorders such as hypertension, kidney stones, cardiovascular disease, and progression of chronic kidney disease.

  3. Micronucleus formation causes perpetual unilateral chromosome inheritance in mouse embryos. (United States)

    Vázquez-Diez, Cayetana; Yamagata, Kazuo; Trivedi, Shardul; Haverfield, Jenna; FitzHarris, Greg


    Chromosome segregation defects in cancer cells lead to encapsulation of chromosomes in micronuclei (MN), small nucleus-like structures within which dangerous DNA rearrangements termed chromothripsis can occur. Here we uncover a strikingly different consequence of MN formation in preimplantation development. We find that chromosomes from within MN become damaged and fail to support a functional kinetochore. MN are therefore not segregated, but are instead inherited by one of the two daughter cells. We find that the same MN can be inherited several times without rejoining the principal nucleus and without altering the kinetics of cell divisions. MN motion is passive, resulting in an even distribution of MN across the first two cell lineages. We propose that perpetual unilateral MN inheritance constitutes an unexpected mode of chromosome missegregation, which could contribute to the high frequency of aneuploid cells in mammalian embryos, but simultaneously may serve to insulate the early embryonic genome from chromothripsis.

  4. Phenotypic profile of expanded NK cells in chronic lymphoproliferative disorders: a surrogate marker for NK-cell clonality. (United States)

    Bárcena, Paloma; Jara-Acevedo, María; Tabernero, María Dolores; López, Antonio; Sánchez, María Luz; García-Montero, Andrés C; Muñoz-García, Noemí; Vidriales, María Belén; Paiva, Artur; Lecrevisse, Quentin; Lima, Margarida; Langerak, Anton W; Böttcher, Sebastian; van Dongen, Jacques J M; Orfao, Alberto; Almeida, Julia


    Currently, the lack of a universal and specific marker of clonality hampers the diagnosis and classification of chronic expansions of natural killer (NK) cells. Here we investigated the utility of flow cytometric detection of aberrant/altered NK-cell phenotypes as a surrogate marker for clonality, in the diagnostic work-up of chronic lymphoproliferative disorders of NK cells (CLPD-NK). For this purpose, a large panel of markers was evaluated by multiparametric flow cytometry on peripheral blood (PB) CD56(low) NK cells from 60 patients, including 23 subjects with predefined clonal (n = 9) and polyclonal (n = 14) CD56(low) NK-cell expansions, and 37 with CLPD-NK of undetermined clonality; also, PB samples from 10 healthy adults were included. Clonality was established using the human androgen receptor (HUMARA) assay. Clonal NK cells were found to show decreased expression of CD7, CD11b and CD38, and higher CD2, CD94 and HLADR levels vs. normal NK cells, together with a restricted repertoire of expression of the CD158a, CD158b and CD161 killer-associated receptors. In turn, NK cells from both clonal and polyclonal CLPD-NK showed similar/overlapping phenotypic profiles, except for high and more homogeneous expression of CD94 and HLADR, which was restricted to clonal CLPD-NK. We conclude that the CD94(hi)/HLADR+ phenotypic profile proved to be a useful surrogate marker for NK-cell clonality.

  5. A nuclear Argonaute promotes multigenerational epigenetic inheritance and germline immortality. (United States)

    Buckley, Bethany A; Burkhart, Kirk B; Gu, Sam Guoping; Spracklin, George; Kershner, Aaron; Fritz, Heidi; Kimble, Judith; Fire, Andrew; Kennedy, Scott


    Epigenetic information is frequently erased near the start of each new generation. In some cases, however, epigenetic information can be transmitted from parent to progeny (multigenerational epigenetic inheritance). A particularly notable example of this type of epigenetic inheritance is double-stranded RNA-mediated gene silencing in Caenorhabditis elegans. This RNA-mediated interference (RNAi) can be inherited for more than five generations. To understand this process, here we conduct a genetic screen for nematodes defective in transmitting RNAi silencing signals to future generations. This screen identified the heritable RNAi defective 1 (hrde-1) gene. hrde-1 encodes an Argonaute protein that associates with small interfering RNAs in the germ cells of progeny of animals exposed to double-stranded RNA. In the nuclei of these germ cells, HRDE-1 engages the nuclear RNAi defective pathway to direct the trimethylation of histone H3 at Lys 9 (H3K9me3) at RNAi-targeted genomic loci and promote RNAi inheritance. Under normal growth conditions, HRDE-1 associates with endogenously expressed short interfering RNAs, which direct nuclear gene silencing in germ cells. In hrde-1- or nuclear RNAi-deficient animals, germline silencing is lost over generational time. Concurrently, these animals exhibit steadily worsening defects in gamete formation and function that ultimately lead to sterility. These results establish that the Argonaute protein HRDE-1 directs gene-silencing events in germ-cell nuclei that drive multigenerational RNAi inheritance and promote immortality of the germ-cell lineage. We propose that C. elegans use the RNAi inheritance machinery to transmit epigenetic information, accrued by past generations, into future generations to regulate important biological processes.

  6. The association between polyploidy and clonal reproduction in diploid and tetraploid Chamerion angustifolium. (United States)

    Baldwin, Sarah J; Husband, Brian C


    Clonal reproduction is associated with the incidence of polyploidy in flowering plants. This pattern may arise through selection for increased clonality in polyploids compared to diploids to reduce mixed-ploidy mating. Here, we test whether clonal reproduction is greater in tetraploid than diploid populations of the mixed-ploidy plant, Chamerion angustifolium, through an analysis of the size and spatial distribution of clones in natural populations using AFLP genotyping and a comparison of root bud production in a greenhouse study. Natural tetraploid populations (N = 5) had significantly more AFLP genotypes (x¯ = 10.8) than diploid populations (x¯ = 6.0). Tetraploid populations tended to have fewer ramets per genotype and fewer genotypes with >1 ramet. In a spatial autocorrelation analysis, ramets within genotypes were more spatially aggregated in diploid populations than in tetraploid populations. In the greenhouse, tetraploids allocated 90.4% more dry mass to root buds than diploids, but tetraploids produced no more root buds and 44% fewer root buds per unit root mass than diploids. Our results indicate that clonal reproduction is significant in most populations, but tetraploid populations are not more clonal than diploids, nor are their clones more spatially aggregated. As a result, tetraploids may be less sheltered from mixed-ploidy mating and diploids more exposed to inbreeding, the balance of which could influence the establishment of tetraploids in diploid populations.

  7. Clonal diversity of Clintonia udensis Mey. populations and its correlation with ecological factors

    Institute of Scientific and Technical Information of China (English)


    The clonal diversity of Clintonia udensis Mey.was detected by ISSR markers among 16 populations,and its correlation with ecological factors was analyzed as well in this work.Results showed that individuals(clonal ramets)per genotype were 1.12 and 1.149 at population and species levels,respectively,and that the 16 populations were all multiclonal.The detected genotypes were localized,without exception,within populations but demonstrated relatively high clonal differentiation among populations.The clonal diversity of the studied populations was high,with the average Simpson’s index of 0.975,while the genets showed a clonal architecture of"guerilla".The population genetic diversities revealed by genet were consistent with those by ramet,further confirming their genetic differentiation among populations.And its genotype diversity within populations probably resulted largely from the frequent seedling regeneration and self-compatibility.In addition,the correlation analysis further revealed that,among the ecological factors,Simpson’s index of C.udensis had a significant positive correlation(P<0.05)with pH values in the soil but not others.

  8. Clonal architecture of secondary acute myeloid leukemia defined by single-cell sequencing.

    Directory of Open Access Journals (Sweden)

    Andrew E O Hughes


    Full Text Available Next-generation sequencing has been used to infer the clonality of heterogeneous tumor samples. These analyses yield specific predictions-the population frequency of individual clones, their genetic composition, and their evolutionary relationships-which we set out to test by sequencing individual cells from three subjects diagnosed with secondary acute myeloid leukemia, each of whom had been previously characterized by whole genome sequencing of unfractionated tumor samples. Single-cell mutation profiling strongly supported the clonal architecture implied by the analysis of bulk material. In addition, it resolved the clonal assignment of single nucleotide variants that had been initially ambiguous and identified areas of previously unappreciated complexity. Accordingly, we find that many of the key assumptions underlying the analysis of tumor clonality by deep sequencing of unfractionated material are valid. Furthermore, we illustrate a single-cell sequencing strategy for interrogating the clonal relationships among known variants that is cost-effective, scalable, and adaptable to the analysis of both hematopoietic and solid tumors, or any heterogeneous population of cells.

  9. Leukemia-Associated Somatic Mutations Drive Distinct Patterns of Age-Related Clonal Hemopoiesis

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    Thomas McKerrell


    Full Text Available Clonal hemopoiesis driven by leukemia-associated gene mutations can occur without evidence of a blood disorder. To investigate this phenomenon, we interrogated 15 mutation hot spots in blood DNA from 4,219 individuals using ultra-deep sequencing. Using only the hot spots studied, we identified clonal hemopoiesis in 0.8% of individuals under 60, rising to 19.5% of those ≥90 years, thus predicting that clonal hemopoiesis is much more prevalent than previously realized. DNMT3A-R882 mutations were most common and, although their prevalence increased with age, were found in individuals as young as 25 years. By contrast, mutations affecting spliceosome genes SF3B1 and SRSF2, closely associated with the myelodysplastic syndromes, were identified only in those aged >70 years, with several individuals harboring more than one such mutation. This indicates that spliceosome gene mutations drive clonal expansion under selection pressures particular to the aging hemopoietic system and explains the high incidence of clonal disorders associated with these mutations in advanced old age.

  10. Low clonal propagation in Atlantic and Mediterranean populations of the red gorgonian Paramuricea clavata (Octocorallia

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    Joanna Pilczynska


    Full Text Available Clonal propagation is a common feature of benthic marine organisms. In the present study, we investigated the contribution of clonal reproduction in the red gorgonian Paramuricea clavata. Mediterranean populations of P. clavata were severely affected by mass mortality events caused by increased water temperature in 1999 and 2003. The populations are characterized by slow growth and episodic recruitment, but after the observed mortalities, an unexpectedly high recovery rate was observed in the severely affected populations from the Ligurian Sea, NW Mediterranean. Ten years after the last mortality event, we investigated the contribution of clonal propagation in populations from the Ligurian Sea, where some populations were highly affected by mass mortality events, and from the Atlantic, where mortality was never observed. All individuals were genotyped for nine microsatellite loci. The contribution of clonal reproduction varied from 0% to 13% and did not differ significantly between affected and unaffected populations. We confirm by using genetic markers that clonal propagation in P. clavata is not common, and that the contribution of clones is too low to play an important role in red gorgonian reproduction and cannot contribute to population recovery at sites that have been affected by mass mortality events.

  11. Study on Clonal Growth Pattern of Sabina vulgaris in Mu Us Sandland

    Institute of Scientific and Technical Information of China (English)

    Zhang Guosheng; Liu Haidong; Liu Meizhen; Wang Linhe; Zhu Jinzhao; Jirigele


    The clonal growth pattern of Sabina vulgaris, a coniferous clonal plant in Mu Us sandland, Inner Mongolia Autonomous Region was surveyed. The results showed that with the stolon extending, internode length and branching angle decreased, the branching intensity increased gradually within the 3 m range from the edge of the shrub to its center along the stolon. Internode length, branching intensity and branching angle were 5.9 cm, 4.4 and 55.3°in the shrub, and 1.6 cm, 13.7 and 38.3°at the edge of the shrub, respectively. The clonal architecture exhibited plasticity. The internode length, branching intensity and ramet length changed with an exponential model with extention of the stolon. The stolon of S. vulgaris was monopodial branching, and each ramet should possess more than 3 adventitious roots. Ramets could take on the phenomenon of "self-thinning" with clonal growth. There was a prior grade in allocation of the nutrients gained from heterogeneous space. The clonal architecture of S. vulgaris was the "mixed" type.

  12. Body size and clonality consequences for sexual reproduction in a perennial herb of Brazilian rupestrian grasslands. (United States)

    Demetrio, G R; Coelho, F F; Barbosa, M E A


    Body size is one of the most important factors regarding herbaceous perennial plants life-histories, and several fitness components of these organisms are related to size. Clonal plants show distinct kinds of reproduction and can develop offspring by sexual or asexual ways. We aimed to understand how body size affects Comanthera nivea (Eriocaulaceae) sexual reproduction and to verify how clonal growth is related to flower head production in this species. We sampled 600 rosettes in rupestrian grasslands and performed linear regression analysis between body size and number of produced flower heads. We also compared the flower head production between isolated rosettes and rosettes within clones. Our results showed that body size was significantly related, but explained only a small part of flower head production. The flower head production was higher in rosettes within clones than in isolated ones. The clones presented a rosette or a small group of rosettes that concentrated the sexual reproduction. Clonality was positively associated with sexual reproduction. Clonality can represent an important way of allowing the persistence of plants by sexual reproduction in markedly seasonal stressful environments. The cases of clonality enhancing the sexual reproduction must be considered and put in focus on reproductive biology research.

  13. Environmentally selected aphid variants in clonality context display differential patterns of methylation in the genome.

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    Claude Pasquier

    Full Text Available Heritability of acquired phenotypic traits is an adaptive evolutionary process that appears more complex than the basic allele selection guided by environmental pressure. In insects, the trans-generational transmission of epigenetic marks in clonal and/or sexual species is poorly documented. Aphids were used as a model to explore this feature because their asexual phase generates a stochastic and/or environment-oriented repertoire of variants. The a priori unchanged genome in clonal individuals prompts us to hypothesize whether covalent methyl DNA marks might be associated to the phenotypic variability and fitness selection. The full differential transcriptome between two environmentally selected clonal variants that originated from the same founder mother was mapped on the entire genomic scaffolds, in parallel with the methyl cytosine distribution. Data suggest that the assortments of heavily methylated DNA sites are distinct in these two clonal phenotypes. This might constitute an epigenetic mechanism that confers the robust adaptation of insect species to various environments involving clonal reproduction.

  14. Maternally-inherited diabetes with deafness (MIDD) and hyporeninemic hypoaldosteronism. (United States)

    Mory, Patricia B; Santos, Marcia C dos; Kater, Claudio E; Moisés, Regina S


    Maternally-inherited diabetes with deafness (MIDD) is a rare form of monogenic diabetes that results, in most cases, from an A-to-G transition at position 3243 of mitochondrial DNA (m.3243A>G) in the mitochondrial-encoded tRNA leucine (UUA/G) gene. As the name suggests, this condition is characterized by maternally-inherited diabetes and bilateral neurosensory hearing impairment. A characteristic of mitochondrial cytopathies is the progressive multisystemic involvement with the development of more symptoms during the course of the disease. We report here the case of a patient with MIDD who developed hyporeninemic hypoaldosteronism.

  15. Identification and validation of highly frequent CpG island hypermethylation in colorectal adenomas and carcinomas. (United States)

    Oster, Bodil; Thorsen, Kasper; Lamy, Philippe; Wojdacz, Tomasz K; Hansen, Lise Lotte; Birkenkamp-Demtröder, Karin; Sørensen, Karina D; Laurberg, Søren; Orntoft, Torben F; Andersen, Claus L


    In our study, whole-genome methylation arrays were applied to identify novel genes with tumor specific DNA methylation of promoter CpG islands in pre-malignant and malignant colorectal lesions. Using a combination of Illumina HumanMethylation27 beadchips, Methylation-Sensitive High Resolution Melting (MS-HRM) analysis, and Exon arrays (Affymetrix) the DNA methylation pattern of ∼14,000 genes and their transcript levels were investigated in six normal mucosas, six adenomas and 30 MSI and MSS carcinomas. Sixty eight genes with tumor-specific hypermethylation were identified (p mucosas, 12 adenomas, 40 MSS and nine MSI cancer samples. The methylation patterns of 15 selected genes, hypermethylated in adenomas and carcinomas (FLI1, ST6GALNAC5, TWIST1, ADHFE1, JAM2, IRF4, CNRIP1, NRG1 and EYA4), in carcinomas only (ABHD9, AOX1 and RERG), or in MSI but not MSS carcinomas (RAMP2, DSC3 and MLH1) were validated using MS-HRM. Four of these genes (MLH1, AOX1, EYA4 and TWIST1) had previously been reported to be hypermethylated in CRC. Eleven genes, not previously known to be affected by CRC specific hypermethylation, were identified and validated. Inverse correlation to gene expression was observed for six of the 15 genes with Spearman correlation coefficients ranging from -0.39 to -0.60. For six of these genes the altered methylation patterns had a profound transcriptional association, indicating that methylation of these genes may play a direct regulatory role. The hypermethylation changes often occurred already in adenomas, indicating that they may be used as biomarkers for early detection of CRC.

  16. CpG Island Methylator Phenotype and Prognosis of Colorectal Cancer in Northeast China

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    Xia Li


    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.

  17. CpG island methylator phenotype association with upregulated telomerase activity in hepatocellular carcinoma. (United States)

    Zhang, Changsong; Guo, Xianling; Jiang, Guocheng; Zhang, Li; Yang, Yang; Shen, Feng; Wu, Mengchao; Wei, Lixin


    CpG island methylator phenotype (CIMP) involves the targeting of multiple genes by promoter hypermethylation. Telomerase plays an important role in the development of cellular immortality and oncogenesis. To gain insight into the role of epigenetic aberration of telomerase-related genes in hepatocarcinogenesis, we determined a hypermethylation profile in HCC. We examined the promoter methylation status of 9 genes associated with telomerase activity in 120 HCC, 120 cirrhosis tissues and 10 normal liver tissues by methylation-specific PCR. Assay of telomerase activity was by TRAP-ELISA. The frequency of promoter methylation of each gene was P21 63.3%, P15 42.5%, P16 62.5%, P53 14.2%, RB 32.5%, P27 48.3%, WTI 54.2%, E2F-1 70.8% and P300 65.8% of 120 HCC. Methylation status of P21, P15, P16, WTI and E2F-1 was significantly associated with HCC and nontumor tissues (p < 0.05). CIMP+ was detected in 61.7% (74/120) HCC and 15% (18/120) cirrhosis tissues, no CIMP+ was present in normal liver tissues (p < 0.001). A significant difference between CIMP status and metastasis was been found in HCC (p < 0.001). Results showed that 94.6% (70/74) HCC and 55.6% (10/18) cirrhosis patients with CIMP+ show expression of high telomerase activity than 45.5% (10/22) HCC and 6.25% (1/16) cirrhosis patients with CIMP- (p < 0.001). CIMP lead to high levels of expression of telomerase activity through the simultaneous inactivation of multiple genes associated with telomerase activity by concordant methylation.

  18. CpG island methylator phenotype of multigene in serum of sporadic breast carcinoma. (United States)

    Jing, Feng; Yuping, Wang; Yong, Chen; Jie, Luo; Jun, Lu; Xuanbing, Tang; Lihua, Hu


    CpG island methylator phenotype (CIMP) involves methylation targeted toward the promoters of multiple genes. We determined a methylation profile of tumor-related genes in serum of sporadic breast cancer (SBC). The multigene methylation was examined by methylation-specific polymerase chain reaction assay in serum of 50 SBCs and 50 paired nontumors, and CIMP+ was defined as having three genes that are concordantly methylated. The methylation frequency of ten genes in serum of 50 SBCs varied from 10% in FHIT to 74% in RASSF1A. The methylation status of RASSF1A, BRCA1, p16, CDH1, ER, RARbeta2, APC, and DAPK was significantly correlated with SBC and nontumor serum (P < 0.05). Methylation of at least one gene was found in 92% SBC; CIMP was more frequent in SBC than nontumor serum (P < 0.001). There was a significant association between CIMP and methylation of RASSF1A, BRCA1, p16, CDH1, ER, RARbeta2, APC, and DAPK (P < 0.05); the methylation link profile of CDH1, RASSF1A, BRCA1, and RARbeta2 as breast cancer marker may contribute high sensitivity (90%) and specificity (88%). ER and RARbeta2 methylation was associated with elevated serum CA153 levels in 39 SBC samples with CIMP+ (P < 0.05). Multivariate analysis showed that living area of patients was found to provide independent prognostic information associated with a relative risk of tumor recurrence of 5.3. Multigene-specific methylation profile in serum was association with the recurrence risk of rural SBC, and positive correlation of CIMP can serve as a promising molecular marker of SBC.

  19. CpG oligodeoxynucleotides inhibit tumor growth and reverse the immunosuppression caused by the therapy with 5-fluorouracil in murine hepatoma

    Institute of Scientific and Technical Information of China (English)

    Xian-Song Wang; Zhen Sheng; You-Bing Ruan; Yang Guang; Mu-Lan Yang


    AIM: To investigate the effect of CpG-containing oligodeoxynucleotides (CpG ODN) alone or in combination with the chemotherapeutic agent 5-fluorouracil (5-FU) on tumor growth and whether CpG ODN can reverse the immunosuppression caused by the chemotherapy with 5-FU in murine hepatoma model.METHODS: Hepatoma model was established by subcutaneous inoculation with hepatoma-22 (H22) cells into the right flank of BALB/c mice. Mice with tumor were treated by peritumoral injection of CpG ODN alone or in combination with subcutaneous injection of 5-FU. Tumor size was quantified regularly. Serum levels of IL-12 and IFN-γ in mice were assayed by enzyme-linked immunosorbent assay (ELISA). The lytic capacity of splenic NK cells was tested by lactate dehydrogenase release assay.RESULTS: Peritumoral injection of CpG ODN alone or in combination with subcutaneous injection of 5-FU, and the treatment with 5-FU alone all led to significant inhibition of hepatoma growth. The mean tumor volumes fell by 46.66% in mice injected with CpG ODN, 68.34% in the 5-FU treated mice, and 70.23% in mice treated with the combination of CpG ODN and 5-FU than in controls. There was no significant difference in tumor size between 5-FUtreated mice and mice treated with the combination of 5-FU and CpG ODN (P>0.05). The serum levels of IL-12and IFN-γ of mice treated with CpG ODN alone (IL-12:464.50±24.37 pg/mL; IFN-γ:134.20±25.76 pg/mL) or with the co-administration of CpG ODN and 5-FU (IL-12:335.83±28.74 pg/mL; IFN-γ:111.00±5.33 pg/mL)were significantly higher than that of controls (IL-12:237.50±45.31 pg/mL; IFN-γ: 56.75±8.22 pg/mL). The production of IL-12 and IFN-γwas suppressed moderately in 5-FU-treated mice (IL-12:166.67±53.22 pg/mL;53.33±16.98 pg/mL) compared to control mice (P>0.05),whereas the combination of CpG ODN and 5-FU significantly increased the serum levels of IL-12 and IFN-γ compared to 5-FU alone (P<0.05). The NK cell killing activity in CpG ODNtreated mice (44.04

  20. Different Growth Promoting Effects of Endophytic Bacteria on Invasive and Native Clonal Plants (United States)

    Dai, Zhi-Cong; Fu, Wei; Wan, Ling-Yun; Cai, Hong-Hong; Wang, Ning; Qi, Shan-Shan; Du, Dao-Lin


    The role of the interactions between endophytes and alien plants has been unclear yet in plant invasion. We used a completely germ-free culture system to quantify the plant growth-promoting (PGP) effects of endophytic bacteria Bacillus sp. on aseptic seedlings of Wedelia trilobata and of its native clonal congener W. chinensis. The endophytic bacteria did not affect the growth of W. chinensis, but they significantly promoted the growth of W. trilobata. With the PGP effects of endophytic bacteria, relative change ratios of the clonal traits and the ramets’ growth traits of W. trilobata were significantly greater than those of W. chinensis. Our results indicate that the growth-promoting effects of endophytes may differ between invasive and native clonal plants, and the endophytes of invasive plant may be host-specific to facilitate plant invasion. PMID:27252722