Ruler Arrays Reveal Haploid Genomic Structural Variation

Despite the known relevance of genomic structural variants to pathogen behavior, cancer, development, and evolution, certain repeat based structural variants may evade detection by existing high-throughput techniques. Here, we present ruler arrays, a technique to detect genomic structural variants including insertions and deletions (indels), duplications, and translocations. A ruler array exploits DNA polymerase’s processivity to detect physical distances between defined genomic sequences regardless of the intervening sequence. The method combines a sample preparation protocol, tiling genomic microarrays, and a new computational analysis. The analysis of ruler array data from two genomic samples enables the identification of structural variation between the samples. In an empirical test between two closely related haploid strains of yeast ruler arrays detected 78% of the structural variants larger than 100 bp.United States. National Institutes of Health (Grant R01GM069676

Effect of fixed-dose subcutaneous reslizumab on asthma exacerbations in patients with severe uncontrolled asthma and corticosteroid sparing in patients with oral corticosteroid-dependent asthma : results from two phase 3, randomised, double-blind, placebo-controlled trials

BACKGROUND: Reslizumab 3 mg/kg administered intravenously is approved for the treatment of severe eosinophilic asthma. We assessed the safety and efficacy of subcutaneous reslizumab 110 mg in two trials in patients with uncontrolled severe asthma and increased blood eosinophils. The aim was to establish whether subcutaneous reslizumab 110 mg can reduce exacerbation rates in these patients (study 1) or reduce maintenance oral corticosteroid dose in patients with corticosteroid-dependent asthma (study 2). METHODS: Both studies were randomised, double-blind, placebo-controlled, phase 3 studies. Entry criteria for study 1 were uncontrolled severe asthma, two or more asthma exacerbations in the previous year, a blood eosinophil count of 300 cells per μL or more (including no more than 30% patients with an eosinophil count <400 cells/μL), and at least a medium dose of inhaled corticosteroids with one or more additional asthma controllers. Patients in study 2 had severe asthma, a blood eosinophil count of 300 cells per μL or more, daily maintenance oral corticosteroid (prednisone 5-40 mg, or equivalent), and high-dose inhaled corticosteroids plus another controller. Patients were randomly assigned (1:1) to subcutaneous reslizumab (110 mg) or placebo once every 4 weeks for 52 weeks in study 1 and 24 weeks in study 2. Patients and investigators were masked to treatment assignment. Primary efficacy outcomes were frequency of exacerbations during 52 weeks in study 1 and categorised percentage reduction in daily oral corticosteroid dose from baseline to weeks 20-24 in study 2. Primary efficacy analyses were by intention to treat, and safety analyses included all patients who received at least one dose of study treatment. These studies are registered with ClinicalTrials.gov, NCT02452190 (study 1) and NCT02501629 (study 2). FINDINGS: Between Aug 12, 2015, and Jan 31, 2018, 468 patients in study 1 were randomly assigned to placebo (n=232) or subcutaneous reslizumab (n=236), and 177 in study 2 to placebo (n=89) or subcutaneous reslizumab (n=88). In study 1, we found no significant difference in the exacerbation rate between reslizumab and placebo in the intention-to-treat population (rate ratio 0·79, 95% CI 0·56-1·12; p=0·19). Subcutaneous reslizumab reduced exacerbation frequency compared with placebo in the subgroup of patients with blood eosinophil counts of 400 cells per μL or more (0·64, 95% CI 0·43-0·95). Greater reductions in annual exacerbation risk (p=0·0035) and longer time to first exacerbation were observed for patients with higher trough serum reslizumab concentrations. In study 2, we found no difference between placebo and fixed-dose subcutaneous reslizumab in categorised percentage reduction in daily oral corticosteroid dose (odds ratio for a lower category of oral corticosteroid use in the reslizumab group vs the placebo group, 1·23, 95% CI 0·70-2·16; p=0·47). The frequency of adverse events and serious adverse events with reslizumab were similar to those with placebo in both studies. INTERPRETATION: Fixed-dose (110 mg) subcutaneous reslizumab was not effective in reducing exacerbation frequency in patients with uncontrolled asthma and increased blood eosinophils (≥300 cells/μL), or in reducing the daily maintenance oral corticosteroid dose in patients with oral corticosteroid-dependent severe eosinophilic asthma. Higher exposures than those observed with 110 mg subcutaneous reslizumab are required to achieve maximal efficacy. FUNDING: Teva Branded Pharmaceutical Products R&D

Counting Orbifolds

We present several methods of counting the orbifolds C^D/Gamma. A correspondence between counting orbifold actions on C^D, brane tilings, and toric diagrams in D-1 dimensions is drawn. Barycentric coordinates and scaling mechanisms are introduced to characterize lattice simplices as toric diagrams. We count orbifolds of C^3, C^4, C^5, C^6 and C^7. Some remarks are made on closed form formulas for the partition function that counts distinct orbifold actions.Comment: 69 pages, 9 figures, 24 tables; minor correction

Ефективність антихелікобактерних комплексів у хворих на пептичну виразку, асоційовану з хелікобактеріозом і оцінка їх впливу на стан слизового бар’єра гастродуоденальної зони

Мета - вивчити у хворих на пептичну виразку (ПВ), асоційовану з хелікобактеріозом (HP), терапевтичну ефективність антихелікобактерних комплексів (АХБК), а також їх влив на стан метаболічних процесів у слизовому бар’єрі гастродуоденальної зони

New CRISPR Mutagenesis Strategies Reveal Variation in Repair Mechanisms among Fungi

We have created new vectors for clustered regularly interspaced short palindromic repeat (CRISPR) mutagenesis in Candida albicans, Saccharomyces cerevisiae, Candida glabrata, and Naumovozyma castellii These new vectors permit a comparison of the requirements for CRISPR mutagenesis in each of these species and reveal different dependencies for repair of the Cas9 double-stranded break. Both C. albicans and S. cerevisiae rely heavily on homology-directed repair, whereas C. glabrata and N. castellii use both homology-directed and nonhomologous end-joining pathways. The high efficiency of these vectors permits the creation of unmarked deletions in each of these species and the recycling of the dominant selection marker for serial mutagenesis in prototrophs. A further refinement, represented by the "Unified" Solo vectors, incorporates Cas9, guide RNA, and repair template into a single vector, thus enabling the creation of vector libraries for pooled screens. To facilitate the design of such libraries, we have identified guide sequences for each of these species with updated guide selection algorithms.IMPORTANCE CRISPR-mediated genome engineering technologies have revolutionized genetic studies in a wide range of organisms. Here we describe new vectors and guide sequences for CRISPR mutagenesis in the important human fungal pathogens C. albicans and C. glabrata, as well as in the related yeasts S. cerevisiae and N. castellii The design of these vectors enables efficient serial mutagenesis in each of these species by leaving few, if any, exogenous sequences in the genome. In addition, we describe strategies for the creation of unmarked deletions in each of these species and vector designs that permit the creation of vector libraries for pooled screens. These tools and strategies promise to advance genetic engineering of these medically and industrially important species.National Institutes of Health (U.S.) (Grant GM035010)National Institutes of Health (U.S.) (Grant GM118135)National Institutes of Health (U.S.) (Grant R15AI130950

Y-systems, Q-systems, and N=2 supersymmetric QFT

We review the connection between Y- and Q-systems and the BPS spectra of 4D script N = 2 supersymmetric QFTs. For each finite BPS chamber of an script N = 2 model which is UV superconformal, one gets a periodic Y-system, while for each finite BPS chamber of an asymptotically-free script N = 2 QFT one gets a Q-system i.e. a rational recursion all whose solutions satisfy a linear recursion with constant coefficients (depending on the initial conditions). For instance, the classical ADE Y-systems of Zamolodchikov correspond to the ADE Argyres-Douglas script N = 2 SCFTs, while the usual ADE Q-systems correspond to pure script N = 2 SYM. After having motivated the correspondence both from the QFT and the thermodynamical Bethe ansatz sides, and having introduced the basic tricks of the trade, we exploit the connection to construct and solve new Y- and Q-systems. In particular,we present the new Y-systems associated to the E6, E7, E8 Minahan-Nemeshanski SCFTs and to the D2 (G ) SCFTs. We also present new Q-systems corresponding to SYM coupled to specific matter systems such that the YM \u3b2-function remains negative. \ua9 2014 IOP Publishing Ltd

On Arnold's 14 `exceptional' N=2 superconformal gauge theories

We study the four-dimensional superconformal N=2 gauge theories engineered by the Type IIB superstring on Arnold's 14 exceptional unimodal singularities (a.k.a. Arnold's strange duality list), thus extending the methods of 1006.3435 to singularities which are not the direct sum of minimal ones. In particular, we compute their BPS spectra in several `strongly coupled' chambers. From the TBA side, we construct ten new periodic Y-systems, providing additional evidence for the existence of a periodic Y-system for each isolated quasi-homogeneous singularity with $\hat c<2$ (more generally, for each N=2 superconformal theory with a finite BPS chamber whose chiral primaries have dimensions of the form N/l).Comment: 73 pages, 7 figure

Transcriptome-wide Mapping Reveals Widespread Dynamic-Regulated Pseudouridylation of ncRNA and mRNA

Pseudouridine is the most abundant RNA modification, yet except for a few well-studied cases, little is known about the modified positions and their function(s). Here, we develop Ψ-seq for transcriptome-wide quantitative mapping of pseudouridine. We validate Ψ-seq with spike-ins and de novo identification of previously reported positions and discover hundreds of unique sites in human and yeast mRNAs and snoRNAs. Perturbing pseudouridine synthases (PUS) uncovers which pseudouridine synthase modifies each site and their target sequence features. mRNA pseudouridinylation depends on both site-specific and snoRNA-guided pseudouridine synthases. Upon heat shock in yeast, Pus7p-mediated pseudouridylation is induced at >200 sites, and PUS7 deletion decreases the levels of otherwise pseudouridylated mRNA, suggesting a role in enhancing transcript stability. rRNA pseudouridine stoichiometries are conserved but reduced in cells from dyskeratosis congenita patients, where the PUS DKC1 is mutated. Our work identifies an enhanced, transcriptome-wide scope for pseudouridine and methods to dissect its underlying mechanisms and function

Diffuse light and galaxy interactions in the core of nearby clusters

The kinematics of the diffuse light in the densest regions of the nearby clusters can be unmasked using the planetary nebulae (PNs) as probes of the stellar motions. The position-velocity diagrams around the brightest cluster galaxies (BCGs) identify the relative contributions from the outer halos and the intracluster light (ICL), defined as the light radiated by the stars floating in the cluster potential. The kinematics of the ICL can then be used to asses the dynamical status of the nearby cluster cores and to infer their formation histories. The cores of the Virgo and Coma are observed to be far from equilibrium, with mergers currently on-going, while the ICL properties in the Fornax and Hydra clusters show the presence of sub-components being accreted in their cores, but superposed to an otherwise relaxed population of stars. Finally the comparison of the observed ICL properties with those predicted from Lambda-CDM simulations indicates a qualitative agreement and provides insights on the ICL formation. Both observations and simulations indicate that BCG halos and ICL are physically distinct components, with the ``hotter" ICL dominating at large radial distances from the BCGs halos as the latter become progressively fainter.Comment: 14 pages, 5 figures. Invited review to appear in the proceedings of "Galaxies and their masks" eds. Block, D.L., Freeman, K.C. and Puerari, I., 2010, Springer (New York

Supersymmetric Gauge Theories, Intersecting Branes and Free Fermions

We show that various holomorphic quantities in supersymmetric gauge theories can be conveniently computed by configurations of D4-branes and D6-branes. These D-branes intersect along a Riemann surface that is described by a holomorphic curve in a complex surface. The resulting I-brane carries two-dimensional chiral fermions on its world-volume. This system can be mapped directly to the topological string on a large class of non-compact Calabi-Yau manifolds. Inclusion of the string coupling constant corresponds to turning on a constant B-field on the complex surface, which makes this space non-commutative. Including all string loop corrections the free fermion theory is elegantly formulated in terms of holonomic D-modules that replace the classical holomorphic curve in the quantum case.Comment: 67 pages, 6 figure