944 research outputs found

    Introduction to the special section on dependable network computing

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    Dependable network computing is becoming a key part of our daily economic and social life. Every day, millions of users and businesses are utilizing the Internet infrastructure for real-time electronic commerce transactions, scheduling important events, and building relationships. While network traffic and the number of users are rapidly growing, the mean-time between failures (MTTF) is surprisingly short; according to recent studies, in the majority of Internet backbone paths, the MTTF is 28 days. This leads to a strong requirement for highly dependable networks, servers, and software systems. The challenge is to build interconnected systems, based on available technology, that are inexpensive, accessible, scalable, and dependable. This special section provides insights into a number of these exciting challenges

    Expand+Functional selection and systematic analysis of intronic splicing elements identify active sequence motifs and associated splicing factors

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    Despite the critical role of pre-mRNA splicing in generating proteomic diversity and regulating gene expression, the sequence composition and function of intronic splicing regulatory elements (ISREs) have not been well elucidated. Here, we employed a high-throughput in vivo Screening PLatform for Intronic Control Elements (SPLICE) to identify 125 unique ISRE sequences from a random nucleotide library in human cells. Bioinformatic analyses reveal consensus motifs that resemble splicing regulatory elements and binding sites for characterized splicing factors and that are enriched in the introns of naturally occurring spliced genes, supporting their biological relevance. In vivo characterization, including an RNAi silencing study, demonstrate that ISRE sequences can exhibit combinatorial regulatory activity and that multiple trans-acting factors are involved in the regulatory effect of a single ISRE. Our work provides an initial examination into the sequence characteristics and function of ISREs, providing an important contribution to the splicing code

    Reprogramming Cellular Behavior with RNA Controllers Responsive to Endogenous Proteins

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    Synthetic genetic devices that interface with native cellular pathways can be used to change natural networks to implement new forms of control and behavior. The engineering of gene networks has been limited by an inability to interface with native components. We describe a class of RNA control devices that overcome these limitations by coupling increased abundance of particular proteins to targeted gene expression events through the regulation of alternative RNA splicing. We engineered RNA devices that detect signaling through the nuclear factor ĪŗB and Wnt signaling pathways in human cells and rewire these pathways to produce new behaviors, thereby linking disease markers to noninvasive sensing and reprogrammed cellular fates. Our work provides a genetic platform that can build programmable sensing-actuation devices enabling autonomous control over cellular behavior

    The maximal tubes under the deformations of a class of 3-dimensional hyperbolic cone-manifolds

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    Recently, Hodgson and Kerckhoff found a small bound on Dehn surgered 3-manifolds from hyperbolic knots not admitting hyperbolic structures using deformations of hyperbolic cone-manifolds. They asked whether the area normalized meridian length squared of maximal tubular neighborhoods of the singular locus of the cone-manifold is decreasing and that summed with the cone angle squared is increasing as we deform the cone-angles. We confirm this near 0 cone-angles for an infinite family of hyperbolic cone-manifolds obtained by Dehn surgeries along the Whitehead link complements. The basic method is based on explicit holonomy computations using the A-polynomials and finding the maximal tubes. One of the key tool is the Taylor expression of a geometric component of the zero set of the A-polynomial in terms of the cone-angles. We also show a sequence of Taylor expressions for Dehn surgered manifolds converges to one for the limit hyperbolic manifold.Comment: 27 pages, 10 figure

    Dimension of the Torelli group for Out(F_n)

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    Let T_n be the kernel of the natural map from Out(F_n) to GL(n,Z). We use combinatorial Morse theory to prove that T_n has an Eilenberg-MacLane space which is (2n-4)-dimensional and that H_{2n-4}(T_n,Z) is not finitely generated (n at least 3). In particular, this recovers the result of Krstic-McCool that T_3 is not finitely presented. We also give a new proof of the fact, due to Magnus, that T_n is finitely generated.Comment: 27 pages, 9 figure

    Computing CMB Anisotropy in Compact Hyperbolic Spaces

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    The measurements of CMB anisotropy have opened up a window for probing the global topology of the universe on length scales comparable to and beyond the Hubble radius. For compact topologies, the two main effects on the CMB are: (1) the breaking of statistical isotropy in characteristic patterns determined by the photon geodesic structure of the manifold and (2) an infrared cutoff in the power spectrum of perturbations imposed by the finite spatial extent. We present a completely general scheme using the regularized method of images for calculating CMB anisotropy in models with nontrivial topology, and apply it to the computationally challenging compact hyperbolic topologies. This new technique eliminates the need for the difficult task of spatial eigenmode decomposition on these spaces. We estimate a Bayesian probability for a selection of models by confronting the theoretical pixel-pixel temperature correlation function with the COBE-DMR data. Our results demonstrate that strong constraints on compactness arise: if the universe is small compared to the `horizon' size, correlations appear in the maps that are irreconcilable with the observations. If the universe is of comparable size, the likelihood function is very dependent upon orientation of the manifold wrt the sky. While most orientations may be strongly ruled out, it sometimes happens that for a specific orientation the predicted correlation patterns are preferred over the conventional infinite models.Comment: 15 pages, LaTeX (IOP style included), 3 color figures (GIF) in separate files. Minor revision to match the version accepted in Class. Quantum Grav.: Proc. of Topology and Cosmology, Cleveland, 1997. The paper can be also downloaded from http://www.cita.utoronto.ca/~pogosyan/cwru_proc.ps.g

    The Effect of Fungi on the Flavor and Color of Tomato Juice

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    Author Institution: The Ohio State University, Columbus, Ohi

    In1-ghrelin splicing variant is associated with reduced disease-free survival of breast cancer patients and increases malignancy of breast cancer cells lines

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    OXFORD UNIVERSITY: This is a pre-copyedited, author-produced version of an article accepted for publication in Carcinogenesis following peer review. The version of record David RincĆ³n-FernĆ”ndez, Michael D Culler, Natia Tsomaia, Gema Moreno-Bueno, RaĆŗl M Luque, Manuel D Gahete, Justo P CastaƱo; In1-ghrelin splicing variant is associated with reduced disease-free survival of breast cancer patients and increases malignancy of breast cancer cells lines, Carcinogenesis, Volume 39, Issue 3, 8 March 2018, Pages 447ā€“457, https://doi.org/10.1093/carcin/bgx146Ghrelin gene generates several variants that regulate multiple pathophysiological functions, including tumor-related processes. In1-ghrelin is a splicing variant that was previously shown to be overexpressed in breast cancer (BCa), where it correlated with proliferation markers; however, its possible association with clinical outcome of BCa patients and underlying mechanisms are still unknown. To address this issue, expression levels and clinical associations of In1-ghrelin were analyzed in a cohort of 117 BCa samples. Additionally, a battery of cellular and molecular assays was implemented using two BCa cell lines (MCF-7 and MDA-MB-231), wherein the role of In1-ghrelin on proliferation, migration, dedifferentiation and signaling pathways was explored. The results generated revealed that high expression of In1-ghrelin in BCa samples was associated with lymph node metastasis and reduced disease-free survival. Indeed, In1-ghrelin overexpression stimulated proliferation and migration in MCF-7 and MDA-MB-231 cells. Similar results were found by treating MDA-MB-231 and MCF-7 with In1- ghrelin-derived peptides. Conversely, In1-ghrelin silencing decreased proliferation and migration capacities of MDA-MB-231. Furthermore, In1-ghrelin (but not ghrelin) overexpression increased the capacity to form mammospheres in both cell lines. These effects could be associated with activation of MAPK-ERK, Jag1/Notch, Wnt/Ī²-catenin and/or TGF-Ī²1 pathways. Altogether, our data indicate that In1-ghrelin could play relevant functional roles in the regulation of BCa development and progression and may provide insights to identify novel biomarkers and new therapeutic approaches for this pathology.BIO-0139, CTS-1406, PI-639-2012, PI-0541-2013 (Junta de Andalucia), BFU2013-43282-R, BFU2016-80360-R (MINECO), PI13-00651, PI16/00264 (Proyectos de InvestigaciĆ³n en Salud FIS, funded by Instituto de Salud Carlos III), GETNE Grant 2014, Merck Serono Grant 2013 and CIBERobn (to RML and JPC); PI13/00132, RETICC RD12/0036/0007, CIBERonc and S2010/BMD-2303 (to GMB
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