Massively Parallel Interrogation of Aptamer Sequence, Structure and Function

BACKGROUND: Optimization of high affinity reagents is a significant bottleneck in medicine and the life sciences. The ability to synthetically create thousands of permutations of a lead high-affinity reagent and survey the properties of individual permutations in parallel could potentially relieve this bottleneck. Aptamers are single stranded oligonucleotides affinity reagents isolated by in vitro selection processes and as a class have been shown to bind a wide variety of target molecules. METHODOLOGY/PRINCIPAL FINDINGS: High density DNA microarray technology was used to synthesize, in situ, arrays of approximately 3,900 aptamer sequence permutations in triplicate. These sequences were interrogated on-chip for their ability to bind the fluorescently-labeled cognate target, immunoglobulin E, resulting in the parallel execution of thousands of experiments. Fluorescence intensity at each array feature was well resolved and shown to be a function of the sequence present. The data demonstrated high intra- and inter-chip correlation between the same features as well as among the sequence triplicates within a single array. Consistent with aptamer mediated IgE binding, fluorescence intensity correlated strongly with specific aptamer sequences and the concentration of IgE applied to the array. CONCLUSION AND SIGNIFICANCE: The massively parallel sequence-function analyses provided by this approach confirmed the importance of a consensus sequence found in all 21 of the original IgE aptamer sequences and support a common stem:loop structure as being the secondary structure underlying IgE binding. The microarray application, data and results presented illustrate an efficient, high information content approach to optimizing aptamer function. It also provides a foundation from which to better understand and manipulate this important class of high affinity biomolecules

Pathophysiology, Diagnosis, and Treatment

Coronary artery aneurysms (CAAs) are uncommon and describe a localized dilatation of a coronary artery segment more than 1.5-fold compared with adjacent normal segments. The incidence of CAAs varies from 0.3 to 5.3%. Ever since the dawn of the interventional era, CAAs have been increasingly diagnosed on coronary angiography. Causative factors include atherosclerosis, Takayasu arteritis, congenital disorders, Kawasaki disease (KD), and percutaneous coronary intervention. The natural history of CAAs remains unclear; however, several recent studies have postulated the underlying molecular mechanisms of CAAs, and genome-wide association studies have revealed several genetic predispositions to CAA. Controversies persist regarding the management of CAAs, and emerging findings support the importance of an early diagnosis in patients predisposed to CAAs, such as in children with KD. This review aims to summarize the present knowledge of CAAs and collate the recent advances regarding the epidemiology, etiology, pathophysiology, diagnosis, and treatment of this disease

Quark zero modes in intersecting center vortex gauge fields

The zero modes of the Dirac operator in the background of center vortex gauge field configurations in $\R^2$ and $\R^4$ are examined. If the net flux in D=2 is larger than 1 we obtain normalizable zero modes which are mainly localized at the vortices. In D=4 quasi-normalizable zero modes exist for intersecting flat vortex sheets with the Pontryagin index equal to 2. These zero modes are mainly localized at the vortex intersection points, which carry a topological charge of $\pm 1/2$. To circumvent the problem of normalizability the space-time manifold is chosen to be the (compact) torus \T^2 and \T^4, respectively. According to the index theorem there are normalizable zero modes on \T^2 if the net flux is non-zero. These zero modes are localized at the vortices. On \T^4 zero modes exist for a non-vanishing Pontryagin index. As in $\R^4$ these zero modes are localized at the vortex intersection points.Comment: 20 pages, 4 figures, LaTeX2e, references added, treatment of ideal vortices on the torus shortene

Infrared Properties of QCD from Dyson-Schwinger equations

I review recent results on the infrared properties of QCD from Dyson-Schwinger equations. The topics include infrared exponents of one-particle irreducible Green's functions, the fixed point behaviour of the running coupling at zero momentum, the pattern of dynamical quark mass generation and properties of light mesons.Comment: 47 pages, 19 figures, Topical Review to be published in J.Phys.G, v2: typos corrected and some references adde

Evaluation of inhibitory effects of benzothiazole and 3-amino-benzothiazolium derivatives on DNA topoisomerase II by molecular modeling studies

There has been considerable interest in DNA topoisomerases over the last decade, as they have been shown to be one of the major cellular targets in anticancer drug development. Previously we synthesized some benzothiazole derivatives and corresponding benzothiazolium forms, and tested their DNA inhibitory activity to develop novel antitumor agents. Among the 12 prepared compounds, compound BM3 (3-aminobenzothiazole-3-ium 4-methylbenzene sulfonate) exhibited extreme topoisomerase II inhibitory activity compared with the reference drug etoposide. We also tried to determine the DNA and enzyme binding abilities of BM3 and found that BM3 acted on topoisomerase II first at low doses, while it had also showed DNA minor groove binding properties at higher doses. In this study the interactions between DNA topoisomerase II and the compounds were examined in detail by molecular modelling studies such as molecular docking and pharmacophore analysis performed using Discovery Studio 3.5. As a result, it was found that benzothiazolium compounds exhibited a totally different mechanism than benzothiazoles by binding to the different amino acids at the active site of the protein molecule. 3-Aminobenzothiazoliums are worthy of carrying onto anticancer studies; BM3 especially would be a good anticancer candidate for preclinical studies. © 2014 Taylor & Francis

Measurement of the CKM angle γ from a combination of B±→Dh± analyses

A combination of three LHCb measurements of the CKM angle γ is presented. The decays B±→D K± and B±→Dπ± are used, where D denotes an admixture of D0 and D0 mesons, decaying into K+K−, π+π−, K±π∓, K±π∓π±π∓, K0Sπ+π−, or K0S K+K− final states. All measurements use a dataset corresponding to 1.0 fb−1 of integrated luminosity. Combining results from B±→D K± decays alone a best-fit value of γ =72.0◦ is found, and confidence intervals are set γ ∈ [56.4,86.7]◦ at 68% CL, γ ∈ [42.6,99.6]◦ at 95% CL. The best-fit value of γ found from a combination of results from B±→Dπ± decays alone, is γ =18.9◦, and the confidence intervals γ ∈ [7.4,99.2]◦ ∪ [167.9,176.4]◦ at 68% CL are set, without constraint at 95% CL. The combination of results from B± → D K± and B± → Dπ± decays gives a best-fit value of γ =72.6◦ and the confidence intervals γ ∈ [55.4,82.3]◦ at 68% CL, γ ∈ [40.2,92.7]◦ at 95% CL are set. All values are expressed modulo 180◦, and are obtained taking into account the effect of D0–D0 mixing

Search for direct stau production in events with two hadronic tau-leptons in root s=13 TeV pp collisions with the ATLAS detector

A search for the direct production of the supersymmetric partners ofτ-leptons (staus) in final stateswith two hadronically decayingτ-leptons is presented. The analysis uses a dataset of pp collisions corresponding to an integrated luminosity of139fb−1, recorded with the ATLAS detector at the LargeHadron Collider at a center-of-mass energy of 13 TeV. No significant deviation from the expected StandardModel background is observed. Limits are derived in scenarios of direct production of stau pairs with eachstau decaying into the stable lightest neutralino and oneτ-lepton in simplified models where the two staumass eigenstates are degenerate. Stau masses from 120 GeV to 390 GeV are excluded at 95% confidencelevel for a massless lightest neutralino

Expected Performance of the ATLAS Experiment - Detector, Trigger and Physics

A detailed study is presented of the expected performance of the ATLAS detector. The reconstruction of tracks, leptons, photons, missing energy and jets is investigated, together with the performance of b-tagging and the trigger. The physics potential for a variety of interesting physics processes, within the Standard Model and beyond, is examined. The study comprises a series of notes based on simulations of the detector and physics processes, with particular emphasis given to the data expected from the first years of operation of the LHC at CERN

Constraints on the χ_(c1) versus χ_(c2) polarizations in proton-proton collisions at √s = 8 TeV

The polarizations of promptly produced χ_(c1) and χ_(c2) mesons are studied using data collected by the CMS experiment at the LHC, in proton-proton collisions at √s=8  TeV. The χ_c states are reconstructed via their radiative decays χ_c → J/ψγ, with the photons being measured through conversions to e⁺e⁻, which allows the two states to be well resolved. The polarizations are measured in the helicity frame, through the analysis of the χ_(c2) to χ_(c1) yield ratio as a function of the polar or azimuthal angle of the positive muon emitted in the J/ψ → μ⁺μ⁻ decay, in three bins of J/ψ transverse momentum. While no differences are seen between the two states in terms of azimuthal decay angle distributions, they are observed to have significantly different polar anisotropies. The measurement favors a scenario where at least one of the two states is strongly polarized along the helicity quantization axis, in agreement with nonrelativistic quantum chromodynamics predictions. This is the first measurement of significantly polarized quarkonia produced at high transverse momentum