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Gnedeva K, Hudspeth AJ, Segil N
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Three-dimensional Organotypic Cultures of Vestibular and Auditory Sensory Organs
JOVE-JOURNAL OF VISUALIZED EXPERIMENTS 2018 JUN; ?(136):? Article e57527
The sensory organs of the inner ear are challenging to study in mammals due to their inaccessibility to experimental manipulation and optical observation. Moreover, although existing culture techniques allow biochemical perturbations, these methods do not provide a means to study the effects of mechanical force and tissue stiffness during development of the inner ear sensory organs. Here we describe a method for three-dimensional organotypic culture of the intact murine utricle and cochlea that overcomes these limitations. The technique for adjustment of a three-dimensional matrix stiffness described here permits manipulation of the elastic force opposing tissue growth. This method can therefore be used to study the role of mechanical forces during inner ear development. Additionally, the cultures permit virus-mediated gene delivery, which can be used for gain- and loss-of-function experiments. This culture method preserves innate hair cells and supporting cells and serves as a potentially superior alternative to the traditional two-dimensional culture of vestibular and auditory sensory organs.
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Hernandez AC, Celik A, Dalchenko M, De Mattia M, Delgado A, Dildick S, Eusebi R, Gilmore J, Huang T, Kamon T, Mueller R, Pakhotin Y, Patel R, Perloff A, Pernie L, Rathjens D, Safonov A, Tatarinov A, Ulmer KA, Akchurin N, Damgov J, De Guio F, Dudero PR, Faulkner J, Gurpinar E, Kunori S, Lamichhane K, Lee SW, Libeiro T, Mengke T, Muthumuni S, Peltola T, Undleeb S, Volobouev I, Wang Z, Greene S, Gurrola A, Janjam R, Johns W, Maguire C, Melo A, Ni H, Padeken K, Sheldon P, Tuo S, Velkovska J, Xu Q, Arenton MW, Barria P, Cox B, Hirosky R, Joyce M, Ledovskoy A, Li H, Neu C, Sinthuprasith T, Wang Y, Wolfe E, Xia F, Harr R, Karchin PE, Poudyal N, Sturdy J, Thapa P, Zaleski S, Brodski M, Buchanan J, Caillol C, Dasu S, Dodd L, Duric S, Gomber B, Grothe M, Herndon M, Herve A, Hussain U, Klabbers P, Lanaro A, Levine A, Long K, Loveless R, Polese G, Ruggles T, Savin A, Smith N, Smith WH, Taylor D, Woods N
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Search for a massive resonance decaying to a pair of Higgs bosons in the four b quark final state in proton-proton collisions at root s=13 TeV
PHYSICS LETTERS B 2018 JUN 10; 781(?):244-269
A search for a massive resonance decaying into a pair of standard model Higgs bosons, in a final state consisting of two b quark-antiquark pairs, is performed. A data sample of proton-proton collisions at a centre-of-mass energy of 13 TeV is used, collected by the CMS experiment at the CERN LHC in 2016, and corresponding to an integrated luminosity of 35.9 fb(-1). The Higgs bosons are highly Lorentz-boosted and are each reconstructed as a single large-area jet. The signal is characterized by a peak in the dijet invariant mass distribution, above a background from the standard model multijet production. The observations are consistent with the background expectations, and are interpreted as upper limits on the products of the s-channel production cross sections and branching fractions of narrow bulk gravitons and radions in warped extra-dimensional models. The limits range from 126 to 1.4 fb at 95% confidence level for resonances with masses between 750 and 3000 GeV, and are the most stringent to date, over the explored mass range. (C) 2018 The Author(s). Published by Elsevier B.V.
Egan BM, Li JX, Davis RA, Fiscella KA, Tobin JN, Jones DW, Sinopoli A
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Differences in primary cardiovascular disease prevention between the 2013 and 2016 cholesterol guidelines and impact of the 2017 hypertension guideline in the United States
JOURNAL OF CLINICAL HYPERTENSION 2018 JUN; 20(6):991-1000
The US Preventive Services Task Force cholesterol guideline recommended statins for fewer adults than the 2013 American College of Cardiology/American Heart Association (ACC/AHA) guideline by setting a higher 10-year atherosclerotic cardiovascular disease threshold (10.0% vs 7.5%) and requiring concomitant diabetes mellitus, hypertension, dyslipidemia, or cigarette smoking. The 2017 ACC/AHA hypertension guideline lowered the hypertension threshold, increasing 2016 guideline statin-eligible adults. Cross-sectional data on US adults aged 40 to 75years enabled estimated numbers for the 2013 guideline and 2016 guideline with hypertension thresholds of 140/90 mm Hg and 130/80 mm Hg, respectively, on: (1) untreated, statin-eligible adults for primary atherosclerotic cardiovascular disease prevention (25.40, 14.72, 15.35 million); (2) atherosclerotic cardiovascular disease events prevented annually (124000, 70852, 73199); (3) number needed to treat (21, 21, 21); and (4) number needed to harm (38, 143, 143) per 1000patient-years for incident diabetes mellitus (42800, 6700, 7100cases per year). Despite the lower hypertension threshold, the 2013 cholesterol guideline qualifies approximately 10 million more adults for statins and prevents approximately 50600 more primary atherosclerotic cardiovascular disease events but induces approximately 35700 more diabetes mellitus cases annually than the 2016 guideline.
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Bose-Einstein correlations in pp, pPb, and PbPb collisions at root s(NN)=0.9-7 TeV
PHYSICAL REVIEW C 2018 JUN 14; 97(6):? Article 064912
Quantum-statistical (Bose-Einstein) two-particle correlations are measured in pp collisions at root s = 0.9, 2.76, and 7 TeV, as well as in pPb and peripheral PbPb collisions at nucleon-nucleon center-of-mass energies of 5.02 and 2.76 TeV, respectively, using the CMS detector at the Large Hadron Collider. Separate analyses are performed for same-sign unidentified charged particles as well as for same-sign pions and kaons identified via their energy loss in the silicon tracker. The characteristics of the one-, two-, and three-dimensional correlation functions are studied as functions of the pair average transverse momentum (k(T)) and the charged-particle multiplicity in the event. For all systems, the extracted correlation radii steadily increase with the event multiplicity, and decrease with increasing k(T). The radii are in the range 1-5 fm, the largest values corresponding to very high multiplicity pPb interactions and to peripheral PbPb collisions with multiplicities similar to those seen in pPb data. It is also observed that the dependencies of the radii on multiplicity and k(T) largely factorize. At the same multiplicity, the radii are relatively independent of the colliding system and center-of-mass energy.
Czarnowicki T, Dohlman AB, Malik K, Antonini D, Bissonnette R, Chan TC, Zhou LS, Wen HC, Estrada Y, Xu H, Bryson C, Shen J, Lala D, Ma'ayan A, McGeehan G, Gregg R, Guttman-Yassky E
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Effect of short-term liver X receptor activation on epidermal barrier features in mild to moderate atopic dermatitis A randomized controlled trial
ANNALS OF ALLERGY ASTHMA & IMMUNOLOGY 2018 JUN; 120(6):631-640.e11
Background: Liver X receptors (LXRs) are involved in maintaining epidermal barrier and suppressing inflammatory responses in model systems. The LXR agonist VTP-38543 showed promising results in improving barrier function and inflammatory responses in model systems. Objective: To assess the safety, tolerability, cellular and molecular changes, and clinical efficacy of the topical VTP-38543 in adults with mild to moderate atopic dermatitis (AD). Methods: A total of 104 ambulatory patients with mild to moderate AD were enrolled in this randomized, double-blind, vehicle-controlled trial between December 2015 and September 2016. VTP-38543 cream in 3 concentrations (0.05%, 0.15%, and 1.0%) or placebo was applied twice daily for 28 days. Pretreatment and post-treatment skin biopsy specimens were obtained from a subset of 33 patients. Changes in SCORing of Atopic Dermatitis, Eczema Area and Severity Index, Investigator's Global Assessment, and tissue biomarkers (by real-time polymerase chain reaction and immunostaining) were evaluated. Results: Topical VTP-38543 was safe and well tolerated. VTP-38543 significantly increased messenger RNA (mRNA) expression of epidermal barrier differentiation (loricrin and filaggrin, P =.02) and lipid (adenosine triphosphate-binding cassette subfamily Gmember 1 and sterol regulatory element binding protein 1c, P <.01) measures and reduced epidermal hyperplasia markers (thickness, keratin 16 mRNA). VTP-38543 non-significantly suppressed cellular infiltrates and down-regulated mRNA expression of several TH17/TH22-related (phosphatidylinositol 3, S100 calcium-binding protein A12) and innate immunity (interleukin 6) markers. Conclusion: Topical VTP-38543 is safe and well tolerated. Its application led to improvement in barrier differentiation and lipids. Longer-term studies are needed to clarify whether a barrier-based approach can induce meaningful suppression of immune abnormalities. Trial Registration: clinicaltrials.gov Identifier: NCT02655679. (c) 2018 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Brunner PM, Israel A, Zhang N, Leonard A, Wen HC, Huynh T, Tran G, Lyon S, Rodriguez G, Immaneni S, Wagner A, Zheng XZ, Estrada YD, Xu H, Krueger JG, Paller AS, Guttman-Yassky E
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Early-onset pediatric atopic dermatitis is characterized by T(H)2/T(H)17/T(H)22-centered inflammation and lipid alterations
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 2018 JUN; 141(6):2094-2106
Background: Although atopic dermatitis (AD) often starts in early childhood, detailed tissue profiling of early-onset AD in children is lacking, hindering therapeutic development for this patient population with a particularly high unmet need for better treatments. Objective: We sought to globally profile the skin of infants with AD compared with that of adults withAD and healthy control subjects. Methods: We performed microarray, RT-PCR, and fluorescence microscopy studies in infants and young children (< 5 years old) with early-onset AD (< 6 months disease duration) compared with age-matched control subjects and adults with longstanding AD. Results: Transcriptomic analyses revealed profound differences between pediatric patients with early-onset versus adult patients with longstanding AD in not only lesional but also nonlesional tissues. Although both patient populations harbored T(H)2-centered inflammation, pediatric AD also showed significant T(H)17/T(H)22 skewing but lacked the T(H)1 upregulation that characterizes adult AD. Pediatric AD exhibited relatively normal expression of epidermal differentiation and cornification products, which is downregulated in adults with AD. Defects in the lipid barrier (eg, ELOVL fatty acid elongase 3 [ELOVL3] and diacylglycerol o-acyltransferase 2 [DGAT2]) and tight junction regulation (eg, claudins 8 and 23) were evident in both groups. However, some lipid-associated mediators (eg, fatty acyl-CoA reductase 2 and fatty acid 2-hydroxylase) showed preferential downregulation in pediatric AD, and lipid barrier genes (FA2H and DGAT2) showed inverse correlations with transepidermal water loss, a functional measure of the epidermal barrier. Conclusions: Skin samples from children and adult patients with AD share lipid metabolism and tight junction alterations, but epidermal differentiation complex defects are only present in adult AD, potentially resulting from chronic immune aberration that is not yet present in early-onset disease.
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Search for excited quarks of light and heavy flavor in gamma plus jet final states in proton-proton collisions at root s=13 TeV
PHYSICS LETTERS B 2018 JUN 10; 781(?):390-411
A search is presented for excited quarks of light and heavy flavor that decay to gamma + jet final states. The analysis is based on data corresponding to an integrated luminosity of 35.9 fb(-1) collected by the CMS experiment in proton-proton collisions at root s = 13 TeV at the LHC. A signal would appear as a resonant contribution to the invariant mass spectrum of the gamma + jet system, above the background expected from standard model processes. No resonant excess is found, and upper limits are set on the product of the excited quark cross section and its branching fraction as a function of its mass. These are the most stringent limits to date in the gamma + jet final state, and exclude excited light quarks with masses below 5.5 TeV and excited b quarks with masses below 1.8 TeV, assuming standard model like coupling strengths. (C) 2018 The Author(s). Published by Elsevier B.V.
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Search for the flavor-changing neutral current interactions of the top quark and the Higgs boson which decays into a pair of b quarks at root s=13 TeV
JOURNAL OF HIGH ENERGY PHYSICS 2018 JUN 20; ?(6):? Article 102
A search for flavor-changing neutral currents (FCNC) in events with the top quark and the Higgs boson is presented. The Higgs boson decay to a pair of b quarks is considered. The data sample corresponds to an integrated luminosity of 35.9 fb(-1) recorded by the CMS experiment at the LHC in proton-proton collisions at root s = 13TeV. Two channels are considered: single top quark FCNC production in association with the Higgs boson (pp -> tH), and top quark pair production with FCNC decay of the top quark (t -> qH). Final states with one isolated lepton and at least three reconstructed jets, among which at least two are associated with b quarks, are studied. No significant deviation is observed from the predicted background. Observed (expected) upper limits at 95% confidence level are set on the branching fractions of top quark decays, B(t -> uH) < 0.47% (0.34%) and B(t -> cH) < 0.47% (0.44%), assuming a single nonzero FCNC coupling.
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Tevatron Run II combination of the effective leptonic electroweak mixing angle
PHYSICAL REVIEW D 2018 JUN 28; 97(11):? Article 112007
Drell-Yan lepton pairs produced in the process p (p) over bar -> l(+)l(-) + X through an intermediate gamma*/Z boson have an asymmetry in their angular distribution related to the spontaneous symmetry breaking of the electroweak force and the associated mixing of its neutral gauge bosons. The CDF and D0 experiments have measured the effective-leptonic electroweak mixing parameter sin(2) theta(lept)(eff) using electron and muon pairs selected from the full Tevatron proton-antiproton data sets collected in 2001-2011, corresponding to 9-10 fb(-1) of integrated luminosity. The combination of these measurements yields the most precise result from hadron colliders, sin(2)theta(lept)(eff) = 0.23148 +/- 0.00033. This result is consistent with, and approaches in precision, the best measurements from electron-positron colliders. The standard model inference of the on-shell electroweak mixing parameter sin(2) theta(W), or equivalently the W-boson mass M-W, using the ZFITTER software package yields sin(2) theta(W) = 0.22324 +/- 0.00033 or equivalently, M-W = 80.367 +/- 0.017 GeV/c(2).
Huang TT, Lan YW, Ko YF, Chen CM, Lai HC, Ojcius DM, Martel J, Young JD, Chong KY
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Antrodia cinnamomea produces anti-angiogenic effects by inhibiting the VEGFR2 signaling pathway
JOURNAL OF ETHNOPHARMACOLOGY 2018 JUN 28; 220(?):239-249
Ethnopharmacological relevance: The medicinal mushroom Antrodia cinnamomea has been used to treat cancer but its anti-angiogenic effects have not been studied in detail. Aim of the study: The main objective of this study was to determine the molecular mechanism of activity underlying the anti-angiogenic effects of A. cinnamomea. Materials and methods: The effects of an A. cinnamomea ethanol extract (ACEE) on cell migration and microvessel formation were investigated in endothelial cells in vitro and Matrigel plugs implanted into mice in vivo. Activation of intracellular signaling pathways was examined using Western blotting. Protein expression was assessed using immunohistochemistry in a mouse model of lung metastasis. Results: We show that treatment with ACEE inhibits cell migration and tube formation in human umbilical vein endothelial cells (HUVECs). ACEE suppresses phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2) and expression of pro-angiogenic kinases in vascular endothelial growth factor (VEGF)-treated HUVECs, in addition to reducing expression of Janus kinase 2 (JAK2) and phosphorylation of signal transducer and activator of transcription 3 (STAT3). ACEE treatment inhibits VEGF-induced microvessel formation in Matrigel plugs in vivo. In addition, ACEE significantly reduces VEGFR2 expression in Lewis lung carcinoma cells and downregulates the expression of cluster of differentiation 31 (CD31) and VEGFR2 in murine lung metastases. Conclusion: These results indicate that A. cinnamomea produces anti-angiogenic effects by inhibiting the VEGFR2 signaling pathway.