Literature-based discovery of diabetes- and ROS-related targets

Abstract Background Reactive oxygen species (ROS) are known mediators of cellular damage in multiple diseases including diabetic complications. Despite its importance, no comprehensive database is currently available for the genes associated with ROS. Methods We present ROS- and diabetes-related targets (genes/proteins) collected from the biomedical literature through a text mining technology. A web-based literature mining tool, SciMiner, was applied to 1,154 biomedical papers indexed with diabetes and ROS by PubMed to identify relevant targets. Over-represented targets in the ROS-diabetes literature were obtained through comparisons against randomly selected literature. The expression levels of nine genes, selected from the top ranked ROS-diabetes set, were measured in the dorsal root ganglia (DRG) of diabetic and non-diabetic DBA/2J mice in order to evaluate the biological relevance of literature-derived targets in the pathogenesis of diabetic neuropathy. Results SciMiner identified 1,026 ROS- and diabetes-related targets from the 1,154 biomedical papers (http://jdrf.neurology.med.umich.edu/ROSDiabetes/). Fifty-three targets were significantly over-represented in the ROS-diabetes literature compared to randomly selected literature. These over-represented targets included well-known members of the oxidative stress response including catalase, the NADPH oxidase family, and the superoxide dismutase family of proteins. Eight of the nine selected genes exhibited significant differential expression between diabetic and non-diabetic mice. For six genes, the direction of expression change in diabetes paralleled enhanced oxidative stress in the DRG. Conclusions Literature mining compiled ROS-diabetes related targets from the biomedical literature and led us to evaluate the biological relevance of selected targets in the pathogenesis of diabetic neuropathy.http://deepblue.lib.umich.edu/bitstream/2027.42/78315/1/1755-8794-3-49.xmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/78315/2/1755-8794-3-49-S7.XLShttp://deepblue.lib.umich.edu/bitstream/2027.42/78315/3/1755-8794-3-49-S10.XLShttp://deepblue.lib.umich.edu/bitstream/2027.42/78315/4/1755-8794-3-49-S8.XLShttp://deepblue.lib.umich.edu/bitstream/2027.42/78315/5/1755-8794-3-49-S3.XLShttp://deepblue.lib.umich.edu/bitstream/2027.42/78315/6/1755-8794-3-49-S1.XLShttp://deepblue.lib.umich.edu/bitstream/2027.42/78315/7/1755-8794-3-49-S4.XLShttp://deepblue.lib.umich.edu/bitstream/2027.42/78315/8/1755-8794-3-49-S2.XLShttp://deepblue.lib.umich.edu/bitstream/2027.42/78315/9/1755-8794-3-49-S12.XLShttp://deepblue.lib.umich.edu/bitstream/2027.42/78315/10/1755-8794-3-49-S11.XLShttp://deepblue.lib.umich.edu/bitstream/2027.42/78315/11/1755-8794-3-49-S9.XLShttp://deepblue.lib.umich.edu/bitstream/2027.42/78315/12/1755-8794-3-49-S5.XLShttp://deepblue.lib.umich.edu/bitstream/2027.42/78315/13/1755-8794-3-49-S6.XLShttp://deepblue.lib.umich.edu/bitstream/2027.42/78315/14/1755-8794-3-49.pdfPeer Reviewe

Rab3D is critical for secretory granule maturation in PC12 cells.

Neuropeptide- and hormone-containing secretory granules (SGs) are synthesized at the trans-Golgi network (TGN) as immature secretory granules (ISGs) and complete their maturation in the F-actin-rich cell cortex. This maturation process is characterized by acidification-dependent processing of cargo proteins, condensation of the SG matrix and removal of membrane and proteins not destined to mature secretory granules (MSGs). Here we addressed a potential role of Rab3 isoforms in these maturation steps by expressing their nucleotide-binding deficient mutants in PC12 cells. Our data show that the presence of Rab3D(N135I) decreases the restriction of maturing SGs to the F-actin-rich cell cortex, blocks the removal of the endoprotease furin from SGs and impedes the processing of the luminal SG protein secretogranin II. This strongly suggests that Rab3D is implicated in the subcellular localization and maturation of ISGs

Calogero-Sutherland Approach to Defect Blocks

Extended objects such as line or surface operators, interfaces or boundaries play an important role in conformal field theory. Here we propose a systematic approach to the relevant conformal blocks which are argued to coincide with the wave functions of an integrable multi-particle Calogero-Sutherland problem. This generalizes a recent observation in 1602.01858 and makes extensive mathematical results from the modern theory of multi-variable hypergeometric functions available for studies of conformal defects. Applications range from several new relations with scalar four-point blocks to a Euclidean inversion formula for defect correlators.Comment: v2: changes for clarit

Induced vertical disparity effects on local and global stereopsis

Purpose: Although significant amounts of vertical misalignment could have a noticeable effect on visual performance, there is no conclusive evidence about the effect of very small amount of vertical disparity on stereopsis and binocular vision. Hence, the aim of this study was to investigate the effects of induced vertical disparity on local and global stereopsis at near. Materials and Methods: Ninety participants wearing best-corrected refraction had local and global stereopsis tested with 0.5 and 1.0 prism diopter (Δ) vertical prism in front of their dominant and non-dominant eye in turn. This was compared to local and global stereopsis in the same subjects without vertical prism. Data were analyzed in SPSS.17 software using the independent samples T and the repeated measures ANOVA tests. Results: Induced vertical disparity decreases local and global stereopsis. This reduction is greater when vertical disparity is induced in front of the non-dominant eye and affects global more than local stereopsis. Repeated measures ANOVA showed differences in the mean stereopsis between the different measured states for local and global values. Local stereopsis thresholds were reduced by 10s of arc or less on average with 1.0Δ of induced vertical prism in front of either eye. However, global stereopsis thresholds were reduced by over 100s of arc by the same 1.0Δ of induced vertical prism. Conclusion: Induced vertical disparity affects global stereopsis thresholds by an order of magnitude (or a factor of 10) more than local stereopsis. Hence, using a test that measures global stereopsis such as the TNO is more sensitive to vertical misalignment than a test such as the Stereofly that measures local stereopsis. © 2014 Informa Healthcare USA, Inc. All rights reserved: reproduction in whole or part not permitted

Unwinding of a cholesteric liquid crystal and bidirectional surface anchoring

We examine the influence of bidirectional anchoring on the unwinding of a planar cholesteric liquid crystal induced by the application of a magnetic field. We consider a liquid crystal layer confined between two plates with the helical axis perpendicular to the substrates. We fixed the director twist on one boundary and allow for bidirectional anchoring on the other by introducing a high-order surface potential. By minimizing the total free energy for the system, we investigate the untwisting of the cholesteric helix as the liquid crystal attempts to align with the magnetic field. The transitions between metastable states occur as a series of pitchjumps as the helix expels quarter or half-turn twists, depending on the relative sizes of the strength of the surface potential and the bidirectional anchoring. We show that secondary easy axis directions can play a significant role in the unwinding of the cholesteric in its transition towards a nematic, especially when the surface anchoring strength is large

Mass hierarchy, 2-3 mixing and CP-phase with Huge Atmospheric Neutrino Detectors

We explore the physics potential of multi-megaton scale ice or water Cherenkov detectors with low ($\sim 1$ GeV) threshold. Using some proposed characteristics of the PINGU detector setup we compute the distributions of events versus neutrino energy $E_\nu$ and zenith angle $\theta_z$, and study their dependence on yet unknown neutrino parameters. The $(E_\nu - \theta_z)$ regions are identified where the distributions have the highest sensitivity to the neutrino mass hierarchy, to the deviation of the 2-3 mixing from the maximal one and to the CP-phase. We evaluate significance of the measurements of the neutrino parameters and explore dependence of this significance on the accuracy of reconstruction of the neutrino energy and direction. The effect of degeneracy of the parameters on the sensitivities is also discussed. We estimate the characteristics of future detectors (energy and angle resolution, volume, etc.) required for establishing the neutrino mass hierarchy with high confidence level. We find that the hierarchy can be identified at $3\sigma$ -- $10\sigma$ level (depending on the reconstruction accuracies) after 5 years of PINGU operation.Comment: 39 pages, 21 figures. Description of Fig.3 correcte

Protein interactions in Xenopus germ plasm RNP particles

Hermes is an RNA-binding protein that we have previously reported to be found in the ribonucleoprotein (RNP) particles of Xenopus germ plasm, where it is associated with various RNAs, including that encoding the germ line determinant Nanos1. To further define the composition of these RNPs, we performed a screen for Hermes-binding partners using the yeast two-hybrid system. We have identified and validated four proteins that interact with Hermes in germ plasm: two isoforms of Xvelo1 (a homologue of zebrafish Bucky ball) and Rbm24b and Rbm42b, both RNA-binding proteins containing the RRM motif. GFP-Xvelo fusion proteins and their endogenous counterparts, identified with antisera, were found to localize with Hermes in the germ plasm particles of large oocytes and eggs. Only the larger Xvelo isoform was naturally found in the Balbiani body of previtellogenic oocytes. Bimolecular fluorescence complementation (BiFC) experiments confirmed that Hermes and the Xvelo variants interact in germ plasm, as do Rbm24b and 42b. Depletion of the shorter Xvelo variant with antisense oligonucleotides caused a decrease in the size of germ plasm aggregates and loosening of associated mitochondria from these structures. This suggests that the short Xvelo variant, or less likely its RNA, has a role in organizing and maintaining the integrity of germ plasm in Xenopus oocytes. While GFP fusion proteins for Rbm24b and 42b did not localize into germ plasm as specifically as Hermes or Xvelo, BiFC analysis indicated that both interact with Hermes in germ plasm RNPs. They are very stable in the face of RNA depletion, but additive effects of combinations of antisense oligos suggest they may have a role in germ plasm structure and may influence the ability of Hermes protein to effectively enter RNP particles

Wnt5a induces ROR1 to complex with HS1 to enhance migration of chronic lymphocytic leukemia cells.

ROR1 (receptor tyrosine kinase-like orphan receptor 1) is a conserved, oncoembryonic surface antigen expressed in chronic lymphocytic leukemia (CLL). We found that ROR1 associates with hematopoietic-lineage-cell-specific protein 1 (HS1) in freshly isolated CLL cells or in CLL cells cultured with exogenous Wnt5a. Wnt5a also induced HS1 tyrosine phosphorylation, recruitment of ARHGEF1, activation of RhoA and enhanced chemokine-directed migration; such effects could be inhibited by cirmtuzumab, a humanized anti-ROR1 mAb. We generated truncated forms of ROR1 and found its extracellular cysteine-rich domain or kringle domain was necessary for Wnt5a-induced HS1 phosphorylation. Moreover, the cytoplamic, and more specifically the proline-rich domain (PRD), of ROR1 was required for it to associate with HS1 and allow for F-actin polymerization in response to Wnt5a. Accordingly, we introduced single amino acid substitutions of proline (P) to alanine (A) in the ROR1 PRD at positions 784, 808, 826, 841 or 850 in potential SH3-binding motifs. In contrast to wild-type ROR1, or other ROR1P→︀A mutants, ROR1P(841)A had impaired capacity to recruit HS1 and ARHGEF1 to ROR1 in response to Wnt5a. Moreover, Wnt5a could not induce cells expressing ROR1P(841)A to phosphorylate HS1 or activate ARHGEF1, and was unable to enhance CLL-cell motility. Collectively, these studies indicate HS1 plays an important role in ROR1-dependent Wnt5a-enhanced chemokine-directed leukemia-cell migration

Evolving Indications for Tricuspid Valve Surgery

More attention has been paid to the mitral valve (MV) than the tricuspid valve (TV), and this relative paucity of data has led to confusion regarding the timing of TV surgery. We review the American College of Cardiology/American Heart Association and European Society of Cardiology guidelines to identify areas of concordance (severe tricuspid regurgitation [TR] in a patient undergoing mitral valve surgery); discordance (less than severe TR but with markers for late TR recurrence such as pulmonary hypertension, a dilated TV annulus, atrial fibrillation, permanent transtricuspid pacing wires and others); and disagreement (surgery for primary TR). We provide our perspective from Northwestern University on these issues and where the guidelines are silent (TR in patients undergoing non-mitral valve operations). Finally, we review recent publications on the results of TV repair and replacement. Although there have been scant publications in the past, there have been more useful publications in recent years to guide our decision making

Large-Theta(13) Perturbation Theory of Neutrino Oscillation for Long-Baseline Experiments

The Cervera et al. formula, the best known approximate formula of neutrino oscillation probability for long-baseline experiments, can be regarded as a second-order perturbative formula with small expansion parameter epsilon \equiv Delta m^2_{21} / Delta m^2_{31} \simeq 0.03 under the assumption s_{13} \simeq epsilon. If theta_{13} is large, as suggested by a candidate nu_{e} event at T2K as well as the recent global analyses, higher order corrections of s_{13} to the formula would be needed for better accuracy. We compute the corrections systematically by formulating a perturbative framework by taking theta_{13} as s_{13} \sim \sqrt{epsilon} \simeq 0.18, which guarantees its validity in a wide range of theta_{13} below the Chooz limit. We show on general ground that the correction terms must be of order epsilon^2. Yet, they nicely fill the mismatch between the approximate and the exact formulas at low energies and relatively long baselines. General theorems are derived which serve for better understanding of delta-dependence of the oscillation probability. Some interesting implications of the large theta_{13} hypothesis are discussed.Comment: Fig.2 added, 23 pages. Matches to the published versio