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"Fire, Andrew"
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عاصفة اللهب
تدور قصة \"عاصفة اللهب\" لأندرو لين حول فقدان شارلوك صديقته ووالدها، حيث يبدو منزلهما وكأن أحدا لم يسكنه قط، وحيث يزعم جيرانهما أنهم لم يسمعوا بهما من قبل إلى حد أن شارلوك يبدأ بالشك بسلامة عقله، إلى أن يقوده مفتاح اللغز إلى اسكتلندا وإن تتبعه هذا المفتاح ورطه في عملية خطف غامضة، حيث اكتشف سارقي جثث ورجلا يزعم أنه يستطيع إحياء الموتى وما من أحد سوى التحري الشاب شارلوك يمكنه حل الأحجية الخطيرة والمربكة التي وقع بها أصدقاؤه وإنقاذهم وهل تعرف شارلوك هولمز؟ فكر في الأمر مجددا.
Book
Intron and gene size expansion during nervous system evolution
Background
The evolutionary radiation of animals was accompanied by extensive expansion of gene and genome sizes, increased isoform diversity, and complexity of regulation.
Results
Here we show that the longest genes are enriched for expression in neuronal tissues of diverse vertebrates and of invertebrates. Additionally, we show that neuronal gene size expansion occurred predominantly through net gains in intron size, with a positional bias toward the 5′ end of each gene.
Conclusions
We find that intron and gene size expansion is a feature of many genes whose expression is enriched in nervous systems. We speculate that unique attributes of neurons may subject neuronal genes to evolutionary forces favoring net size expansion. This process could be associated with tissue-specific constraints on gene function and/or the evolution of increasingly complex gene regulation in nervous systems.
Journal Article
نيران التمرد
\"نيران التمرد\" رواية تجمع بين الغرابة والرعب، ولئن كان الخيال عادة يفتح آفاقا رحبة للسرد، فإنه في هذه الرواية يقترح الكتابة في عوالم مغلقة موصدة للأبواب وليس بإمكان غير شارلوك هولمز فتحها وفي المغامرة الثانية للشاب شارلوك هولمز \"نيران التمرد\" يبدو هنا -في الرواية- على يقين أن البالغين يحفظون الأسرار ولكنه لم يتوقع العثور على المجرم الأكثر شهرة في العالم مقيما في \"ساري\"، بريتش كولومبيا، يبدو، في حين أنه اعتبر ميتا، وشقيقه متورط في الأمر بطريقة ما.
BOOK
Efficient Marker-Free Recovery of Custom Genetic Modifications with CRISPR/Cas9 in Caenorhabditis elegans
Facilitated by recent advances using CRISPR/Cas9, genome editing technologies now permit custom genetic modifications in a wide variety of organisms. Ideally, modified animals could be both efficiently made and easily identified with minimal initial screening and without introducing exogenous sequence at the locus of interest or marker mutations elsewhere. To this end, we describe a coconversion strategy, using CRISPR/Cas9 in which screening for a dominant phenotypic oligonucleotide-templated conversion event at one locus can be used to enrich for custom modifications at another unlinked locus. After the desired mutation is identified among the F1 progeny heterozygous for the dominant marker mutation, F2 animals that have lost the marker mutation are picked to obtain the desired mutation in an unmarked genetic background. We have developed such a coconversion strategy for Caenorhabditis elegans, using a number of dominant phenotypic markers. Examining the coconversion at a second (unselected) locus of interest in the marked F1 animals, we observed that 14–84% of screened animals showed homologous recombination. By reconstituting the unmarked background through segregation of the dominant marker mutation at each step, we show that custom modification events can be carried out recursively, enabling multiple mutant animals to be made. While our initial choice of a coconversion marker [rol-6(su1006)] was readily applicable in a single round of coconversion, the genetic properties of this locus were not optimal in that CRISPR-mediated deletion mutations at the unselected rol-6 locus can render a fraction of coconverted strains recalcitrant to further rounds of similar mutagenesis. An optimal marker in this sense would provide phenotypic distinctions between the desired mutant/+ class and alternative +/+, mutant/null, null/null, and null/+ genotypes. Reviewing dominant alleles from classical C. elegans genetics, we identified one mutation in dpy-10 and one mutation in sqt-1 that meet these criteria and demonstrate that these too can be used as effective conversion markers. Coconversion was observed using a variety of donor molecules at the second (unselected) locus, including oligonucleotides, PCR products, and plasmids. We note that the coconversion approach described here could be applied in any of the variety of systems where suitable coconversion markers can be identified from previous intensive genetic analyses of gain-of-function alleles.
Journal Article
Knaves over queens
As the alien Xenovirus reaches Britain, Prime Minister Sir Winston Churchill, now gifted with extraordinary longevity, joins with Alan Turing to set up a special organization, the Order of the Silver Helix, to outmaneuver the terrifying mutations of the virus in Britain.
BOOK
Direct CRISPR spacer acquisition from RNA by a natural reverse transcriptase–Cas1 fusion protein
The CRISPR (clustered regularly interspaced short palindromic repeat) system provides bacteria with an adaptive immune response. DNA captured from viruses and plasmids by CRISPR-associated protein 1 (Cas1) is used by bacteria to target the invaders' for destruction. Silas et al. discover that certain classes of the Cas1 gene are fused to a reverse transcriptase gene ( RT-Cas1 ) (see the Perspective by Sontheimer and Marraffini). These RT-Cas1 proteins are able to capture and directly incorporate both DNA and RNA into CRISPR loci. RT-Cas1 systems could be effective against parasitic RNA species, or even to modulate bacterial gene expression. Science , this issue p. 10.1126/science.aad4234 ; see also p. 920 A reverse transcriptase activity captures and introduces RNA directly into CRISPR loci. CRISPR systems mediate adaptive immunity in diverse prokaryotes. CRISPR-associated Cas1 and Cas2 proteins have been shown to enable adaptation to new threats in type I and II CRISPR systems by the acquisition of short segments of DNA (spacers) from invasive elements. In several type III CRISPR systems, Cas1 is naturally fused to a reverse transcriptase (RT). In the marine bacterium Marinomonas mediterranea (MMB-1), we showed that a RT-Cas1 fusion protein enables the acquisition of RNA spacers in vivo in a RT-dependent manner. In vitro, the MMB-1 RT-Cas1 and Cas2 proteins catalyze the ligation of RNA segments into the CRISPR array, which is followed by reverse transcription. These observations outline a host-mediated mechanism for reverse information flow from RNA to DNA.
Journal Article
Determinants of nucleosome organization in primary human cells
Nucleosome positions mapped
The organization of nucleosomes across the genome influences gene regulation, and understanding the mechanisms that underlie this organization in different organisms is an active area of research. In this study, genome-wide maps of nucleosome positions in three primary human cell types and
in vitro
have been generated by high-throughput DNA sequencing. Most of the genome exhibits substantial flexibility of nucleosome positions, and a combination of intrinsic sequence-based nucleosome preferences and interactions with non-nucleosomal factors determine nucleosome organization
in vivo
.
Nucleosomes are the basic packaging units of chromatin, modulating accessibility of regulatory proteins to DNA and thus influencing eukaryotic gene regulation. Elaborate chromatin remodelling mechanisms have evolved that govern nucleosome organization at promoters, regulatory elements, and other functional regions in the genome
1
. Analyses of chromatin landscape have uncovered a variety of mechanisms, including DNA sequence preferences, that can influence nucleosome positions
2
,
3
,
4
. To identify major determinants of nucleosome organization in the human genome, we used deep sequencing to map nucleosome positions in three primary human cell types and
in vitro
. A majority of the genome showed substantial flexibility of nucleosome positions, whereas a small fraction showed reproducibly positioned nucleosomes. Certain sites that position
in vitro
can anchor the formation of nucleosomal arrays that have cell type-specific spacing
in vivo
. Our results unveil an interplay of sequence-based nucleosome preferences and non-nucleosomal factors in determining nucleosome organization within mammalian cells.
Journal Article
DNA Polymerase Diversity Reveals Multiple Incursions of Polintons During Nematode Evolution
Abstract
Polintons are double-stranded DNA, virus-like self-synthesizing transposons widely found in eukaryotic genomes. Recent metagenomic discoveries of Polinton-like viruses are consistent with the hypothesis that Polintons invade eukaryotic host genomes through infectious viral particles. Nematode genomes contain multiple copies of Polintons and provide an opportunity to explore the natural distribution and evolution of Polintons during this process. We performed an extensive search of Polintons across nematode genomes, identifying multiple full-length Polinton copies in several species. We provide evidence of both ancient Polinton integrations and recent mobility in strains of the same nematode species. In addition to the major nematode Polinton family, we identified a group of Polintons that are overall closely related to the major family but encode a distinct protein-primed DNA polymerase B (pPolB) that is related to homologs from a different group of Polintons present outside of the Nematoda. Phylogenetic analyses on the pPolBs support the evolutionary scenarios in which these extrinsic pPolBs that seem to derive from Polinton families present in oomycetes and molluscs replaced the canonical pPolB in subsets of Polintons found in terrestrial and marine nematodes, respectively, suggesting interphylum horizontal gene transfers. The pPolBs of the terrestrial nematode and oomycete Polintons share a unique feature, an insertion of an HNH nuclease domain, whereas the pPolBs in the marine nematode Polintons share an insertion of a VSR nuclease domain with marine mollusc pPolBs. We hypothesize that horizontal gene transfer occurs among Polintons from widely different but cohabiting hosts.
Journal Article
Nonsense mRNA suppression via nonstop decay
Nonsense-mediated mRNA decay is the process by which mRNAs bearing premature stop codons are recognized and cleared from the cell. While considerable information has accumulated regarding recognition of the premature stop codon, less is known about the ensuing mRNA suppression. During the characterization of a second, distinct translational surveillance pathway (nonstop mRNA decay), we trapped intermediates in nonsense mRNA degradation. We present data in support of a model wherein nonsense-mediated decay funnels into the nonstop decay pathway in Caenorhabditis elegans. Specifically, our results point to SKI-exosome decay and pelota-based ribosome removal as key steps facilitating suppression and clearance of prematurely-terminated translation complexes. These results suggest a model in which premature stop codons elicit nucleolytic cleavage, with the nonstop pathway disengaging ribosomes and degrading the resultant RNA fragments to suppress ongoing expression.
Journal Article
Six RNA Viruses and Forty-One Hosts: Viral Small RNAs and Modulation of Small RNA Repertoires in Vertebrate and Invertebrate Systems
We have used multiplexed high-throughput sequencing to characterize changes in small RNA populations that occur during viral infection in animal cells. Small RNA-based mechanisms such as RNA interference (RNAi) have been shown in plant and invertebrate systems to play a key role in host responses to viral infection. Although homologs of the key RNAi effector pathways are present in mammalian cells, and can launch an RNAi-mediated degradation of experimentally targeted mRNAs, any role for such responses in mammalian host-virus interactions remains to be characterized. Six different viruses were examined in 41 experimentally susceptible and resistant host systems. We identified virus-derived small RNAs (vsRNAs) from all six viruses, with total abundance varying from \"vanishingly rare\" (less than 0.1% of cellular small RNA) to highly abundant (comparable to abundant micro-RNAs \"miRNAs\"). In addition to the appearance of vsRNAs during infection, we saw a number of specific changes in host miRNA profiles. For several infection models investigated in more detail, the RNAi and Interferon pathways modulated the abundance of vsRNAs. We also found evidence for populations of vsRNAs that exist as duplexed siRNAs with zero to three nucleotide 3' overhangs. Using populations of cells carrying a Hepatitis C replicon, we observed strand-selective loading of siRNAs onto Argonaute complexes. These experiments define vsRNAs as one possible component of the interplay between animal viruses and their hosts.
Journal Article