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Emergence of classicality for primordial fluctuations: Concepts and analogies  [PDF]
C. Kiefer,D. Polarski
Physics , 1998,
Abstract: We clarify the way in which cosmological perturbations of quantum origin, produced during inflation, assume classical properties. Two features play an important role in this process: First, the dynamics of fluctuations which are presently on large cosmological scales leads to a very peculiar state (highly squeezed) that is indistinguishable, in a precise sense, from a classical stochastic process. This holds for almost all initial quantum states. Second, the process of decoherence by interaction with the environment distinguishes the field amplitude basis as a robust pointer basis. We discuss in detail the interplay between these features and use simple analogies such as the free quantum particle to illustrate the main conceptual issues.
Characterization of a Weak Allele of Zebrafish cloche Mutant  [PDF]
Ning Ma, Zhibin Huang, Xiaohui Chen, Fei He, Kun Wang, Wei Liu, Linfeng Zhao, Xiangmin Xu, Wangjun Liao, Hua Ruan, Shenqiu Luo, Wenqing Zhang
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0027540
Abstract: Hematopoiesis is a complicated and dynamic process about which the molecular mechanisms remain poorly understood. Danio rerio (zebrafish) is an excellent vertebrate system for studying hematopoiesis and developmental mechanisms. In the previous study, we isolated and identified a cloche172 (clo172) mutant, a novel allele compared to the original cloche (clo) mutant, through using complementation test and initial mapping. Here, according to whole mount in-situ hybridization, we report that the endothelial cells in clo172 mutant embryos, although initially developed, failed to form the functional vascular system eventually. In addition, further characterization indicates that the clo172 mutant exhibited weaker defects instead of completely lost in primitive erythroid cells and definitive hematopoietic cells compared with the clos5 mutant. In contrast, primitive myeloid cells were totally lost in clo172 mutant. Furthermore, these reappeared definitive myeloid cells were demonstrated to initiate from the remaining hematopoietic stem cells (HSCs) in clo172 mutant, confirmed by the dramatic decrease of lyc in clo172runx1w84x double mutant. Collectively, the clo172 mutant is a weak allele compared to the clos5 mutant, therefore providing a model for studying the early development of hematopoietic and vascular system, as well as an opportunity to further understand the function of the cloche gene.
On the Evolutionary Fate of Mutant Allele at Duplicate Loci: a Theoretical and Simulation Study  [PDF]
Yupeng Cun
Quantitative Biology , 2010,
Abstract: Gene duplications are one of major primary driving forces for evolutionary novelty. We took population genetics models of genes duplicate to study how evolutionary forces acting during the fixation of mutant allele at duplicate loci. We study the fixation time of mutant allele at duplicate loci under double null recessive model (DNR) and haploinsufficient model (HI). And we also investigate how selection coefficients with other evolutionary force influence the fixation frequency of mutant allele at duplicate loci. Our results suggest that the selection plays a role in the evolutionary fate of duplicate genes, and tight linkage would help the mutant allele preserved at duplicate loci. Our theoretical simulation agree with the genomics data analysis result well, that selection, rather than drift, plays a important role in the establishment of duplicate loci, and recombination have a great opportunity to be acted upon selection.
Oncogene Mutations, Copy Number Gains and Mutant Allele Specific Imbalance (MASI) Frequently Occur Together in Tumor Cells  [PDF]
Junichi Soh,Naoki Okumura,William W. Lockwood,Hiromasa Yamamoto,Hisayuki Shigematsu,Wei Zhang,Raj Chari,David S. Shames,Ximing Tang,Calum MacAulay,Marileila Varella-Garcia,T?nu Vooder,Ignacio I. Wistuba,Stephen Lam,Rolf Brekken,Shinichi Toyooka,John D. Minna,Wan L. Lam,Adi F. Gazdar
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0007464
Abstract: Activating mutations in one allele of an oncogene (heterozygous mutations) are widely believed to be sufficient for tumorigenesis. However, mutant allele specific imbalance (MASI) has been observed in tumors and cell lines harboring mutations of oncogenes.
Antiphase Synchronization in a Flagellar-Dominance Mutant of Chlamydomonas  [PDF]
Kyriacos C. Leptos,Kirsty Y. Wan,Marco Polin,Idan Tuval,Adriana I. Pesci,Raymond E. Goldstein
Quantitative Biology , 2013, DOI: 10.1103/PhysRevLett.111.158101
Abstract: Groups of beating flagella or cilia often synchronize so that neighboring filaments have identical frequencies and phases. A prime example is provided by the unicellular biflagellate Chlamydomonas reinhardtii, which typically displays synchronous in-phase beating in a low-Reynolds number version of breaststroke swimming. We report here the discovery that ptx1, a flagellar dominance mutant of C. reinhardtii, can exhibit synchronization in precise antiphase, as in the freestyle swimming stroke. Long-duration high-speed imaging shows that ptx1 flagella switch stochastically between in-phase and antiphase states, and that the latter has a distinct waveform and significantly higher frequency, both of which are strikingly similar to those found during phase slips that stochastically interrupt in-phase beating of the wildtype. Possible mechanisms underlying these observations are discussed.
Allele-Specific Silencing of Mutant Huntingtin in Rodent Brain and Human Stem Cells  [PDF]
Valérie Drouet, Marta Ruiz, Diana Zala, Maxime Feyeux, Gwenna?lle Auregan, Karine Cambon, Laetitia Troquier, Johann Carpentier, Sophie Aubert, Nicolas Merienne, Fany Bourgois-Rocha, Raymonde Hassig, Maria Rey, No?lle Dufour, Frédéric Saudou, Anselme L. Perrier, Philippe Hantraye, Nicole Déglon
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0099341
Abstract: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder resulting from polyglutamine expansion in the huntingtin (HTT) protein and for which there is no cure. Although suppression of both wild type and mutant HTT expression by RNA interference is a promising therapeutic strategy, a selective silencing of mutant HTT represents the safest approach preserving WT HTT expression and functions. We developed small hairpin RNAs (shRNAs) targeting single nucleotide polymorphisms (SNP) present in the HTT gene to selectively target the disease HTT isoform. Most of these shRNAs silenced, efficiently and selectively, mutant HTT in vitro. Lentiviral-mediated infection with the shRNAs led to selective degradation of mutant HTT mRNA and prevented the apparition of neuropathology in HD rat's striatum expressing mutant HTT containing the various SNPs. In transgenic BACHD mice, the mutant HTT allele was also silenced by this approach, further demonstrating the potential for allele-specific silencing. Finally, the allele-specific silencing of mutant HTT in human embryonic stem cells was accompanied by functional recovery of the vesicular transport of BDNF along microtubules. These findings provide evidence of the therapeutic potential of allele-specific RNA interference for HD.
Preferential expression of mutant ABCD1 allele is common in adrenoleukodystrophy female carriers but unrelated to clinical symptoms
Ettore Salsano, Silvia Tabano, Silvia M Sirchia, Patrizia Colapietro, Barbara Castellotti, Cinzia Gellera, Marco Rimoldi, Viviana Pensato, Caterina Mariotti, Davide Pareyson, Monica Miozzo, Graziella Uziel
Orphanet Journal of Rare Diseases , 2012, DOI: 10.1186/1750-1172-7-10
Abstract: To shed light into this topic we assessed the XCI pattern in peripheral blood mononuclear cells (PBMCs) of 30 X-ALD carriers. Since a frequent problem with XCI studies is the underestimation of skewing due to an incomplete sample digestion by restriction enzymes, leading to variable results, we developed a pyrosequencing assay to identify samples completely digested, on which to perform the XCI assay. Pyrosequencing was also used to quantify ABCD1 allele-specific expression. Moreover, very long-chain fatty acid (VLCFA) levels were determined in the same patients.We found severely (≥90:10) or moderately (≥75:25) skewed XCI in 23 out of 30 (77%) X-ALD carriers and proved that preferential XCI is mainly associated with the preferential expression of the mutant ABCD1 allele, irrespective of the manifestation of symptoms. The expression of mutant ABCD1 allele also correlates with plasma VLCFA concentrations.Our results indicate that preferential XCI leads to the favored expression of the mutant ABCD1 allele. This emerges as a general phenomenon in X-ALD carriers not related to the presence of symptoms. Our data support the postulated growth advantage of cells with the preferential expression of the mutant ABCD1 allele, but argue against the use of XCI pattern, ABCD1 allele-specific expression pattern and VLCFA plasma concentration as biomarkers to predict the development of symptoms in X-ALD carriers.X-linked adrenoleukodystrophy (X-ALD, OMIM#300100) encompasses a spectrum of X-linked metabolic diseases due to mutations in the ABCD1 (ATP-Binding Cassette, Subfamily D, Member 1) gene mapping to Xq28. ABCD1 encodes for an integral peroxisomal membrane protein which is hypothesized to be necessary for transferring very long-chain fatty acids (VLCFAs) or their activated metabolites into the peroxisomes, where they are degraded through the beta-oxidation pathway. Hence, X-ALD is biochemically characterized by excessive plasma and tissue accumulation of VLCFAs. It has been sug
A Highly Sensitive Quantitative Real-Time PCR Assay for Determination of Mutant JAK2 Exon 12 Allele Burden  [PDF]
Lasse Kj?r, Maj Westman, Caroline Hasselbalch Riley, Estrid H?gdall, Ole Weis Bjerrum, Hans Hasselbalch
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0033100
Abstract: Mutations in the Janus kinase 2 (JAK2) gene have become an important identifier for the Philadelphia-chromosome negative chronic myeloproliferative neoplasms. In contrast to the JAK2V617F mutation, the large number of JAK2 exon 12 mutations has challenged the development of quantitative assays. We present a highly sensitive real-time quantitative PCR assay for determination of the mutant allele burden of JAK2 exon 12 mutations. In combination with high resolution melting analysis and sequencing the assay identified six patients carrying previously described JAK2 exon 12 mutations and one novel mutation. Two patients were homozygous with a high mutant allele burden, whereas one of the heterozygous patients had a very low mutant allele burden. The allele burden in the peripheral blood resembled that of the bone marrow, except for the patient with low allele burden. Myeloid and lymphoid cell populations were isolated by cell sorting and quantitative PCR revealed similar mutant allele burdens in CD16+ granulocytes and peripheral blood. The mutations were also detected in B-lymphocytes in half of the patients at a low allele burden. In conclusion, our highly sensitive assay provides an important tool for quantitative monitoring of the mutant allele burden and accordingly also for determining the impact of treatment with interferon-α-2, shown to induce molecular remission in JAK2V617F-positive patients, which may be a future treatment option for JAK2 exon 12-positive patients as well.
Allele-Specific RNA Silencing of Mutant Ataxin-3 Mediates Neuroprotection in a Rat Model of Machado-Joseph Disease  [PDF]
Sandro Alves, Isabel Nascimento-Ferreira, Gwenna?lle Auregan, Raymonde Hassig, No?lle Dufour, Emmanuel Brouillet, Maria C. Pedroso de Lima, Philippe Hantraye, Luís Pereira de Almeida, Nicole Déglon
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0003341
Abstract: Recent studies have demonstrated that RNAi is a promising approach for treating autosomal dominant disorders. However, discrimination between wild-type and mutant transcripts is essential, to preserve wild-type expression and function. A single nucleotide polymorphism (SNP) is present in more than 70% of patients with Machado-Joseph disease (MJD). We investigated whether this SNP could be used to inactivate mutant ataxin-3 selectively. Lentiviral-mediated silencing of mutant human ataxin-3 was demonstrated in vitro and in a rat model of MJD in vivo. The allele-specific silencing of ataxin-3 significantly decreased the severity of the neuropathological abnormalities associated with MJD. These data demonstrate that RNAi has potential for use in MJD treatment and constitute the first proof-of-principle for allele-specific silencing in the central nervous system.
An Allele of Sequoia Dominantly Enhances a Trio Mutant Phenotype to Influence Drosophila Larval Behavior  [PDF]
Kathryn E. Dean, April Fields, Marcus J. Geer, Eric C. King, Brian T. Lynch, Rohan R. Manohar, Julianne R. McCall, Katherine C. Palozola, Yan Zhang, Eric C. Liebl
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0084149
Abstract: The transition of Drosophila third instar larvae from feeding, photo-phobic foragers to non-feeding, photo-neutral wanderers is a classic behavioral switch that precedes pupariation. The neuronal network responsible for this behavior has recently begun to be defined. Previous genetic analyses have identified signaling components for food and light sensory inputs and neuropeptide hormonal outputs as being critical for the forager to wanderer transition. Trio is a Rho-Guanine Nucleotide Exchange Factor integrated into a variety of signaling networks including those governing axon pathfinding in early development. Sequoia is a pan-neuronally expressed zinc-finger transcription factor that governs dendrite and axon outgrowth. Using pre-pupal lethality as an endpoint, we have screened for dominant second-site enhancers of a weakly lethal trio mutant background. In these screens, an allele of sequoia has been identified. While these mutants have no obvious disruption of embryonic central nervous system architecture and survive to third instar larvae similar to controls, they retain forager behavior and thus fail to pupariate at high frequency.
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