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41.
Jasmin B Kuemmerle-Deschner Helmut Wittkowski Pascal N Tyrrell Ina Koetter Peter Lohse Katharina Ummenhofer Fabian Reess Sandra Hansmann Assen Koitschev Christoph Deuter Anja Bialkowski Dirk Foell Susanne M Benseler 《Arthritis research & therapy》2013,15(3):R64
Objectives
Muckle-Wells syndrome (MWS) is an autoinflammatory disease characterized by excessive interleukin-1 (IL-1) release, resulting in recurrent fevers, sensorineural hearing loss, and amyloidosis. IL-1 inhibition with anakinra, an IL-1 receptor antagonist, improves clinical symptoms and inflammatory markers. Subclinical disease activity is commonly observed. Canakinumab, a fully human IgG1 anti-IL-1β monoclonal antibody, can abolish excess IL-1β. The study aim was to analyze the efficacy and safety of these two anti-IL-1 therapies.Methods
Two cohorts of patients with severe MWS and confirmed NLRP3 mutation were treated with anakinra and/or canakinumab. Clinical and laboratory features including ESR, CRP, SAA, and the neutrophil marker S100A12 were determined serially. Disease activity was captured by MWS disease activity scores (MWS-DAS). Remission was defined as MWS-DAS ≤5 plus normal CRP and SAA. Treatment efficacy and safety were analyzed.Results
The study included 12 anakinra- and 14 canakinumab-treated patients; the median age was 33.5 years (3.0 years to 72.0 years); 57% were female patients. Both treatment regimens led to a significant reduction of clinical disease activity and inflammatory markers. At last follow-up, 75% of anakinra-treated and 93% of canakinumab-treated patients achieved remission. During follow-up, S100A12 levels mirrored recurrence of disease activity. Both treatment regimens had favorable safety profiles.Conclusions
IL-1 blockade is an effective and safe treatment in MWS patients. MWS-DAS in combination with MWS inflammatory markers provides an excellent monitoring tool set. Canakinumab led to a sustained control of disease activity even after secondary failure of anakinra therapy. S100A12 may be a sensitive marker to detect subclinical disease activity. 相似文献42.
43.
Luna RE Arthanari H Hiraishi H Nanda J Martin-Marcos P Markus MA Akabayov B Milbradt AG Luna LE Seo HC Hyberts SG Fahmy A Reibarkh M Miles D Hagner PR O'Day EM Yi T Marintchev A Hinnebusch AG Lorsch JR Asano K Wagner G 《Cell reports》2012,1(6):689-702
Recognition of the proper start codon on mRNAs is essential for protein synthesis, which requires scanning and involves eukaryotic initiation factors (eIFs) eIF1, eIF1A, eIF2, and eIF5. The carboxyl terminal domain (CTD) of eIF5 stimulates 43S preinitiation complex (PIC) assembly; however, its precise role in scanning and start codon selection has remained unknown. Using nuclear magnetic resonance (NMR) spectroscopy, we identified the binding sites of eIF1 and eIF2β on eIF5-CTD and found that they partially overlapped. Mutating select eIF5 residues in the common interface specifically disrupts interaction with both factors. Genetic and biochemical evidence indicates that these eIF5-CTD mutations impair start codon recognition and impede eIF1 release from the PIC by abrogating eIF5-CTD binding to eIF2β. This study provides mechanistic insight into the role of eIF5-CTD's dynamic interplay with eIF1 and eIF2β in switching PICs from an open to a closed state at start codons. 相似文献
44.
Ryan CJ Roguev A Patrick K Xu J Jahari H Tong Z Beltrao P Shales M Qu H Collins SR Kliegman JI Jiang L Kuo D Tosti E Kim HS Edelmann W Keogh MC Greene D Tang C Cunningham P Shokat KM Cagney G Svensson JP Guthrie C Espenshade PJ Ideker T Krogan NJ 《Molecular cell》2012,46(5):691-704
To date, cross-species comparisons of genetic interactomes have been restricted to small or functionally related gene sets, limiting our ability to infer evolutionary trends. To facilitate a more comprehensive analysis, we constructed a genome-scale epistasis map (E-MAP) for the fission yeast Schizosaccharomyces pombe, providing phenotypic signatures for ~60% of the nonessential genome. Using these signatures, we generated a catalog of 297 functional modules, and we assigned function to 144 previously uncharacterized genes, including mRNA splicing and DNA damage checkpoint factors. Comparison with an integrated genetic interactome from the budding yeast Saccharomyces cerevisiae revealed a hierarchical model for the evolution of genetic interactions, with conservation highest within protein complexes, lower within biological processes, and lowest between distinct biological processes. Despite the large evolutionary distance and extensive rewiring of individual interactions, both networks retain conserved features and display similar levels of functional crosstalk between biological processes, suggesting general design principles of genetic interactomes. 相似文献
45.
Lindqvist L Oberer M Reibarkh M Cencic R Bordeleau ME Vogt E Marintchev A Tanaka J Fagotto F Altmann M Wagner G Pelletier J 《PloS one》2008,3(2):e1583
RNA helicases represent a large family of proteins implicated in many biological processes including ribosome biogenesis, splicing, translation and mRNA degradation. However, these proteins have little substrate specificity, making inhibition of selected helicases a challenging problem. The prototypical DEAD box RNA helicase, eIF4A, works in conjunction with other translation factors to prepare mRNA templates for ribosome recruitment during translation initiation. Herein, we provide insight into the selectivity of a small molecule inhibitor of eIF4A, hippuristanol. This coral-derived natural product binds to amino acids adjacent to, and overlapping with, two conserved motifs present in the carboxy-terminal domain of eIF4A. Mutagenesis of amino acids within this region allowed us to alter the hippuristanol-sensitivity of eIF4A and undertake structure/function studies. Our results provide an understanding into how selective targeting of RNA helicases for pharmacological intervention can be achieved. 相似文献
46.
Wu CW Cheng SF Huang WN Trivedi VD Veeramuthu B Assen B K Wu WG Chang DK 《Biochimica et biophysica acta》2003,1612(1):41-51
Mutations of the glycine residue at the amino terminus of HA2 have been shown to have a large effect on the fusion activity of HA2, the extent of which apparently correlates with the side chain bulkiness of the substituting amino acids. To investigate into the cause of abrogation in fusogenicity and virus-promoted fusion mechanism, we synthesized several peptides in which this glycine was substituted by serine, glutamic acid, or lysine. 1,2-Dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and 1,2-dimyristoyl sn-glycero-3-phosphoglycerol (DMPG) were used as model membranes in the fluorescence, circular dichroism (CD), and FTIR measurements while sodium dodecyl sulfate was used in NMR studies. We found that, for the less active variants, affinity to membrane, degree of solvent dehydration, lipid perturbation, depth of insertion, and helicity were less. Comparison of affinity to membrane bilayer among these analogs revealed that binding of the fusion peptide is determined largely by the hydrophobic effect. Additionally, the orientation is closer to the membrane normal for the wild-type fusion peptide in the helix form while the inactive analogs inserted more parallel to the membrane surface. 相似文献
47.
Merkus D Haitsma DB Fung TY Assen YJ Verdouw PD Duncker DJ 《American journal of physiology. Heart and circulatory physiology》2003,285(1):H424-H433
In dogs, only combined blockade of vasodilator pathways [via adenosine receptors, nitric oxide synthase (NOS) and ATP-sensitive K+ (KATP) channels] results in impairment of metabolic vasodilation, which suggests a redundancy design of coronary flow regulation. Conversely, in swine and humans, blocking KATP channels, adenosine receptors, or NOS each impairs coronary blood flow (CBF) at rest and during exercise. Consequently, we hypothesized that these vasodilators act in parallel rather than in redundancy to regulate CBF in swine. Swine exercised on a treadmill (0-5 km/h), during control and after blockade of KATP channels (with glibenclamide), adenosine receptors [with 8-phenyltheophylline (8-PT)], and/or NOS [with Nomega-nitro-l-arginine (l-NNA)]. l-NNA, 8-PT, and glibenclamide each reduced myocardial O2 delivery and coronary venous O2 tension. These effects of l-NNA, 8-PT, and glibenclamide were not modified by simultaneous blockade of the other vasodilators. Combined blockade of KATP channels and adenosine receptors with or without NOS inhibition was associated with increased H+ production and impaired myocardial function. However, despite an increase in O2 extraction to >90% during administration of l-NNA + 8-PT + glibenclamide, vasodilator reserve could still be recruited during exercise. Thus in awake swine, loss of KATP channels, adenosine, or NO is not compensated for by increased participation of the other two vasodilator mechanisms. These findings suggest a parallel rather than a redundancy design of CBF regulation in the porcine circulation. 相似文献
48.
Chris?W.?Stoddart Mathew?T.?Martin–Iverson Assen?Jablensky Nadezda?UrosevicEmail author 《Mammalian genome》2004,15(11):901-913
Mice of the strain C3H.PRI-Flvr, carrying genetically determined resistance to flaviviruses, have been shown to be more sensitive to the hypothermic effect of dopamine than congenic flavivirus-susceptible C3H/HeJARC mice. In the current study, the greater sensitivity to dopamine-induced hypothermia observed in flavivirus-resistant mice was shown to be dose-dependent, with strain differences being the most prominent at a moderate dose of apomorphine (1 mg/kg). In addition, hypothermic responses to apomorphine were shown to be under developmental regulation; aging increased the potency of apomorphine-induced hypothermia and abrogated strain and sex differences observed in young mice. Linkage analysis of mouse strain-dependent co-inheritance between flavivirus resistance and greater sensitivity to the hypothermic effect of dopamine was performed using two genetically unrelated flavivirus-susceptible and two highly congenic flavivirus-resistant mouse strains in parallel with C3H.PRI-Flvr-and C3H/HeJARC reference strains. This study has revealed a clear segregation between flavivirus resistance conferred by the Flv locus and sensitivity to dopamine-controlled hypothermia conferred by a novel locus, Diht. Parallel studies in F1 and F2 heterozygote mice showed that the high sensitivity to hypothermic effect of dopamine (Dihthigh) is inherited as the Chr5-linked dominant trait. The novel locus, Diht, has been mapped proximal to the Flv locus on a distal part of mouse Chr5 between microsatellite markers D5Mit41 and D5Mit158. 相似文献
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50.
Steady state fluorescence experiments were performed on a 25-mer synthetic peptide incorporated in the phospholipid vesicle to study the role of oligomerization of the fusion peptide in membrane fusion. It was found from fluorescence resonance energy transfer (FRET) that the extent of lipid mixing and the initial mixing rate varied with the fusion peptide concentration in a higher than linear fashion, indicating that the peptide promoted membrane mixing as oligomers. Results of self-quenching of the Rhodamine (Rho) in Rho-labelled peptide incorporated in the phospholipid bilayer indicated that the peptide molecules assembled in the bilayer with an order higher than dimer. The data also revealed that the peptides were not tightly packed in the membrane. Binding affinity measurement monitored by the NBD fluorescence intensity on the fluorophore-labelled fusion peptide supports the notion of self-association of the peptide in the vesicular dispersion. In the sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) experiments, a diffuse band with apparent molecular mass close to a dimeric species of the wild type fusion peptide suggested that the fusion peptides formed loose oligomers under the influence of SDS detergent in the electric field. The result is in contrast to a less fusion-active variant which appears to exhibit less propensity for self-association. 相似文献