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  • 1
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 14 July 2015, Vol.112(28), pp.E3679-88
    Description: Ran is a small GTP-binding protein of the Ras superfamily regulating fundamental cellular processes: nucleo-cytoplasmic transport, nuclear envelope formation and mitotic spindle assembly. An intracellular Ran•GTP/Ran•GDP gradient created by the distinct subcellular localization of its regulators RCC1 and RanGAP mediates many of its cellular effects. Recent proteomic screens identified five Ran lysine acetylation sites in human and eleven sites in mouse/rat tissues. Some of these sites are located in functionally highly important regions such as switch I and switch II. Here, we show that lysine acetylation interferes with essential aspects of Ran function: nucleotide exchange and hydrolysis, subcellular Ran localization, GTP hydrolysis, and the interaction with import and export receptors. Deacetylation activity of certain sirtuins was detected for two Ran acetylation sites in vitro. Moreover, Ran was acetylated by CBP/p300 and Tip60 in vitro and on transferase overexpression in vivo. Overall, this study addresses many important challenges of the acetylome field, which will be discussed.
    Keywords: Ran ; Genetic Code Expansion Concept ; Lysine Acetylation ; Nuclear Cytosolic Transport ; Nucleus ; Protein Processing, Post-Translational ; Lysine -- Metabolism ; Ran Gtp-Binding Protein -- Physiology
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 2
    In: Nature, 2015, Vol.524(7564), p.230
    Description: Cells sense their environment and adapt to it by fine-tuning their transcriptome. Wired into this network of gene expression control are mechanisms to compensate for gene dosage. The increasing use of reverse genetics in zebrafish, and other model systems, has revealed profound differences between the phenotypes caused by genetic mutations and those caused by gene knockdowns at many loci (1-3), an observation previously reported in mouse and Arabidopsis (4-7). To identify the reasons underlying the phenotypic differences between mutants and knockdowns, we generated mutations in zebrafish egfl7, an endothelial extracellular matrix gene of therapeutic interest, as well as in vegfaa. Here we show that egfl7 mutants do not show any obvious phenotypes while animals injected with egfl7 morpholino (morphants) exhibit severe vascular defects. We further observe that egfl7 mutants are less sensitive than their wild-type siblings to Egfl7 knockdown, arguing against residual protein function in the mutants or significant off-target effects of the morpholinos when used at a moderate dose. Comparing egfl7 mutant and morphant proteomes and transcriptomes, we identify a set of proteins and genes that are upregulated in mutants but not in morphants. Among them are extracellular matrix genes that can rescue egfl7 morphants, indicating that they could be compensating for the loss of Egfl7 function in the phenotypically wild-type egfl7 mutants. Moreover, egfl7 CRISPR interference, which obstructs transcript elongation and causes severe vascular defects, does not cause the upregulation of these genes. Similarly, vegfaa mutants but not morphants show an upregulation of vegfab. Taken together, these data reveal the activation of a compensatory network to buffer against deleterious mutations, which was not observed after translational or transcriptional knockdown.
    Keywords: Gene Mutation -- Analysis ; Phenotypes -- Analysis ; Rna -- Analysis;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 3
    Language: English
    In: The Journal of Allergy and Clinical Immunology, February 2016, Vol.137(2), pp.AB161-AB161
    Description: To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.jaci.2015.12.657 Byline: Hendrik Nolte, Greg A. Plunkett, Mirko Bollen, Karin Grosch, Jorgen Nedergaard Larsen, Kaare Lund Author Affiliation: (1) Merck & Co., Inc., Kenilworth, NJ (2) ALK-Abello, Inc, Round Rock, TX (3) ALK, Horsholm, Denmark Article Note: (miscellaneous) 526
    Keywords: Medicine
    ISSN: 0091-6749
    E-ISSN: 1097-6825
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  • 4
    Language: English
    In: Analytical Chemistry, Nov 18, 2014, Vol.86(22), p.11033(5)
    Description: The article describes the quantification of turnover of more than 200 proteins using mass spectrometry with high reproducibility and accuracy by injecting native serum from heavy stable isotope labeled (SIL) mice into nonlabeled recipients. A median of 19.4 h and a total range of 6-70 h were found for calculated half-lives; moreover, similar half-lives for proteins with equal function were observed. The value and effectiveness of SILflood were demonstrated by investigating the impaired serum clearance in beta2-microglobulin (B2M/) deficient mice, and it was found that serum albumin and IgG half-lives were clearly reduced in B2M deficient animals compared to control animals.
    Keywords: Immunoglobulin G – Analysis
    ISSN: 0003-2700
    Source: Cengage Learning, Inc.
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  • 5
    Language: English
    In: The Journal of Allergy and Clinical Immunology, 2011, Vol.127(1), pp.72-80.e2
    Description: Immunotherapy for allergic rhinoconjunctivitis (ARC) in North America is generally administered subcutaneously, but alternative formulations might be safer and more convenient. Trials of sublingual formulations in North America are needed to confirm European efficacy and safety data. We sought to investigate the efficacy and safety of timothy grass allergy immunotherapy tablet (AIT) treatment in North American subjects with ARC. Four hundred thirty-nine adults with grass pollen–induced ARC with or without asthma were randomized to once-daily 2,800 bioequivalent allergen units of standardized grass AIT (oral lyophilisate, , 75,000 standardized quality tablet, containing approximately 15 μg of Phl p 5) or placebo approximately 16 weeks before the 2009 grass pollen season (GPS). The primary end point was the average total combined score of the daily symptom score and the daily medication score during the GPS. Rhinoconjunctivitis Quality of Life Questionnaire with standardized activities (RQLQ[S]) scores, Phl p 5–specific IgG4 levels, and IgE-blocking factor levels were additional end points. Adverse events (AEs) were monitored for safety. Relative to placebo, grass AIT treatment improved total combined scores by 20% (  = .005), daily symptom scores by 18% (  = .02), and RQLQ(S) scores by 17% (  = .02). Daily medication scores were improved by 26% and trended toward significance (  = .08). Phl p 5–specific IgG4 and IgE-blocking factor levels were higher after grass AIT treatment compared with those after placebo at the end of the GPS (  〈 .001). Grass AIT treatment was safe and well tolerated. The majority of AEs were transient mild local reactions with no investigator-diagnosed grass AIT–related serious AEs or reports of anaphylactic shock/respiratory compromise. In the grass AIT group, 1 subject received epinephrine after experiencing a possible grade 1 systemic reaction (local site reactions, chest discomfort, and rash). Timothy grass AIT treatment (cross-reactive with related Pooideae grasses) was demonstrated to be effective, generally safe, and well tolerated in North American adults with grass pollen–induced ARC.
    Keywords: Allergy Immunotherapy Tablet ; Allergic Rhinoconjunctivitis ; Specific Immunotherapy ; Grass Pollen ; Sublingual Immunotherapy ; Medicine
    ISSN: 0091-6749
    E-ISSN: 1097-6825
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  • 6
    Language: English
    In: The Journal of Allergy and Clinical Immunology, 2011, Vol.127(1), pp.64-71.e4
    Description: Allergy immunotherapy tablet (AIT) treatment might be a safe and convenient form of specific immunotherapy but it has not been investigated in North American children and adolescents. We sought to investigate the efficacy and safety of timothy grass AIT treatment in North American children/adolescents with grass pollen–induced allergic rhinoconjunctivitis (ARC) with or without asthma. Three hundred forty-five subjects (5-17 years old) were randomized to once-daily grass AIT treatment (2,800 bioequivalent allergen units, 75,000 standardized quality tablet, approximately 15 μg of Phl p 5) or placebo approximately 16 weeks before the 2009 grass pollen season (GPS). Treatment continued through the GPS. Daily symptoms and allergy rescue medication use were recorded. The primary end point was the total combined score (TCS) of the daily symptom score (DSS) and daily medication score (DMS) for the entire GPS. DSS, DMS, Rhinoconjunctivitis Quality of Life Questionnaire score, and Phl p 5–specific IgG4 and IgE-blocking factor levels were secondary end points. Safety was assessed through adverse events. Eighty-nine percent of subjects were multisensitized. TCS, DSS, DMS, and Rhinoconjunctivitis Quality of Life Questionnaire score versus placebo improved 26% (  = .001), 25% (  = .005), 81% (  = .006), and 18% (  = .04). Phl p 5–specific IgG4 and IgE-blocking factor levels were significantly higher at the peak and end of the GPS (  〈 .001). Treatment was well tolerated. Adverse events were generally mild and transient. Although no investigator-assessed systemic allergic reactions were reported, 1 grass AIT–treated subject experienced an event indicating a systemic reaction (lip angioedema, dysphagia, and cough). Use of once-daily timothy grass AIT treatment effectively treats timothy grass (cross-reactive with Festucoideae grasses) pollen–induced ARC in North American children 5 years and older. Given its convenient administration, lack of dose build-up requirement, safety profile, and efficacy, AIT treatment might become an important addition to the North American ARC treatment armamentarium.
    Keywords: Allergy Immunotherapy Tablet ; Allergic Rhinoconjunctivitis ; Specific Immunotherapy ; Grass Pollen ; Children ; Sublingual Immunotherapy ; Medicine
    ISSN: 0091-6749
    E-ISSN: 1097-6825
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  • 7
    Language: English
    In: Quality of Life Research, 2011, Vol.20(6), pp.903-912
    Description: Byline: Kathleen W. Wyrwich (1), Andrea M. Ireland (1), Prakash Navaratnam (2), Hendrik Nolte (3), Davis F. Gates (3) Keywords: Asthma; Quality of life; Clinical trials; Outcome assessment; Questionnaires; Adolescent Abstract: Background To date, there is limited psychometric evidence on the Asthma Quality of Life Questionnaire (AQLQ12 +) among populations that include adolescents and adults. Objective To provide evidence of the psychometric properties of the AQLQ12+ as a measure of asthma-specific quality of life (QOL) in patients with persistent asthma treated with a combination of inhaled glucocorticoid and long-acting beta2-agonist, as well as explore the predictors of at least a minimally important AQLQ12+ improvement. Methods The psychometric properties of the AQLQ12+ were assessed through post hoc analysis of two large (n = 740 and 778) Phase III, randomized, double-blinded, placebo-controlled efficacy studies of mometasone furoate/formoterol fumarate (MF/F) combination compared with monotherapy in subjects with persistent asthma previously treated with either low-dose or medium-dose inhaled glucocorticoids. Results With 15% and 8% participation from 12- to 17-year olds, blinded trial data demonstrated excellent reproducibility (ICC range: 0.76--0.85) and moderate-to-strong construct validity with other measures of asthma health at baseline and over time for the AQLQ12 +. A greater percentage of the MF/F treatment group (44%) achieved an important change at 26 weeks on the AQLQ12+ compared with formoterol fumarate (F, 23%) and placebo (18%) treatment groups in the low-dose study (P 〈 0.001) and the medium-dose study (50% (MF/F) versus 34% (F) and 23% (placebo) P 〈 0.001). Pre-randomization nighttime awakenings and rescue medications use were significant predictors of AQLQ12+ improvement. Conclusions These findings provide strong support for the measurement properties of the AQLQ12+ among patients with persistent asthma and confidence in the AQLQ12+ improvements demonstrated by the MF/F treatment group. Author Affiliation: (1) United BioSource Corporation, 7101 Wisconsin Avenue, Suite 600, Bethesda, MD, 20814, USA (2) DataMed Solutions LLC, Hilliard, OH, USA (3) Merck Research Laboratories, Kenilworth, NJ, USA Article History: Registration Date: 08/12/2010 Accepted Date: 07/12/2010 Online Date: 24/12/2010
    Keywords: Asthma ; Quality of life ; Clinical trials ; Outcome assessment ; Questionnaires ; Adolescent
    ISSN: 0962-9343
    E-ISSN: 1573-2649
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  • 8
    Language: English
    In: The Journal of Allergy and Clinical Immunology, 2015, Vol.135(2), p.AB281
    Description: To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.jaci.2014.12.1856 Byline: Amarjot Kaur, Domingo Barber, Ziliang Li, Jennifer Maloney, Hendrik Nolte Author Affiliation: (1) Merck & Co., Inc., Whitehouse Station, NJ (2) Universidad San Pablo-CEU, Madrid, Spain Article Note: (miscellaneous) 911
    Keywords: Immunoglobulin E ; Immunotherapy
    ISSN: 0091-6749
    E-ISSN: 10976825
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  • 9
    Language: English
    In: The Journal of Allergy and Clinical Immunology, February 2018, Vol.141(2), pp.AB173-AB173
    Description: Rationale The SQ house dust mite (HDM) SLIT-tablet is approved in North America for treatment of HDM allergic rhinitis with/without conjunctivitis in adults (ODACTRATM, 12 SQ-HDM, ALK, Denmark). Conclusions The background prevalence of EOE is 57/100,000 persons in the US. [...]the prevalence of EoE with SQ HDM SLIT-tablet does not support a potential risk related to treatment at this point in time.
    Keywords: Medicine
    ISSN: 0091-6749
    E-ISSN: 1097-6825
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  • 10
    Language: English
    In: The Journal of Allergy and Clinical Immunology, February 2014, Vol.133(2), pp.AB218-AB218
    Description: Immunotherapy for allergic rhinitis with/without conjunctivitis (AR/C) may exhibit different efficacy characteristics in patients with multiple allergen sensitizations than monosensitized patients. It has been considered that monosensitized patients may benefit more from immunotherapy than polysensitized patients. Evidence from randomized, blinded, placebo-controlled trials of Timothy grass sublingual immunotherapy tablet (SLIT-T) MK-7243 (Merck/ALK-Abelló) indicates that treatment in mono- and polysensitized subjects is equally effective.
    Keywords: Medicine
    ISSN: 0091-6749
    E-ISSN: 1097-6825
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