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991.
Cyclin O (Ccno) functions during deuterosome-mediated centriole amplification of multiciliated cells
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![点击此处可从《The EMBO journal》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Maja C Funk Agata N Bera Tabea Menchen Georg Kuales Kerstin Thriene Soeren S Lienkamp Jörn Dengjel Heymut Omran Marcus Frank Sebastian J Arnold 《The EMBO journal》2015,34(8):1078-1089
Mucociliary clearance and fluid transport along epithelial surfaces are carried out by multiciliated cells (MCCs). Recently, human mutations in Cyclin O (CCNO) were linked to severe airway disease. Here, we show that Ccno expression is restricted to MCCs and the genetic deletion of Ccno in mouse leads to reduced numbers of multiple motile cilia and characteristic phenotypes of MCC dysfunction including severe hydrocephalus and mucociliary clearance deficits. Reduced cilia numbers are caused by compromised generation of centrioles at deuterosomes, which serve as major amplification platform for centrioles in MCCs. Ccno-deficient MCCs fail to sufficiently generate deuterosomes, and only reduced numbers of fully functional centrioles that undergo maturation to ciliary basal bodies are formed. Collectively, this study implicates CCNO as first known regulator of deuterosome formation and function for the amplification of centrioles in MCCs. 相似文献
992.
Nonsyndromic cleft lip with or without cleft palate: Increased burden of rare variants within Gremlin‐1, a component of the bone morphogenetic protein 4 pathway
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![点击此处可从《Birth defects research. Part A, Clinical and molecular teratology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Taofik Al Chawa Kerstin U. Ludwig Heide Fier Bernd Pötzsch Rudolf H. Reich Gül Schmidt Bert Braumann Nikolaos Daratsianos Anne C. Böhmer Hannah Schuencke Margrieta Alblas Nadine Fricker Per Hoffmann Michael Knapp Christoph Lange Markus M. Nöthen Elisabeth Mangold 《Birth defects research. Part A, Clinical and molecular teratology》2014,100(6):493-498
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Catherine Vilchèze Virginie Molle Séverine Carrère-Kremer Jade Leiba Lionel Mourey Shubhada Shenai Grégory Baronian Joann Tufariello Travis Hartman Romain Veyron-Churlet Xavier Trivelli Sangeeta Tiwari Brian Weinrick David Alland Yann Guérardel William R. Jacobs Jr Laurent Kremer 《PLoS pathogens》2014,10(5)
Mycobacterium tuberculosis bacilli display two signature features: acid-fast staining and the capacity to induce long-term latent infections in humans. However, the mechanisms governing these two important processes remain largely unknown. Ser/Thr phosphorylation has recently emerged as an important regulatory mechanism allowing mycobacteria to adapt their cell wall structure/composition in response to their environment. Herein, we evaluated whether phosphorylation of KasB, a crucial mycolic acid biosynthetic enzyme, could modulate acid-fast staining and virulence. Tandem mass spectrometry and site-directed mutagenesis revealed that phosphorylation of KasB occurred at Thr334 and Thr336 both in vitro and in mycobacteria. Isogenic strains of M. tuberculosis with either a deletion of the kasB gene or a kasB_T334D/T336D allele, mimicking constitutive phosphorylation of KasB, were constructed by specialized linkage transduction. Biochemical and structural analyses comparing these mutants to the parental strain revealed that both mutant strains had mycolic acids that were shortened by 4–6 carbon atoms and lacked trans-cyclopropanation. Together, these results suggested that in M. tuberculosis, phosphorylation profoundly decreases the condensing activity of KasB. Structural/modeling analyses reveal that Thr334 and Thr336 are located in the vicinity of the catalytic triad, which indicates that phosphorylation of these amino acids would result in loss of enzyme activity. Importantly, the kasB_T334D/T336D phosphomimetic and deletion alleles, in contrast to the kasB_T334A/T336A phosphoablative allele, completely lost acid-fast staining. Moreover, assessing the virulence of these strains indicated that the KasB phosphomimetic mutant was attenuated in both immunodeficient and immunocompetent mice following aerosol infection. This attenuation was characterized by the absence of lung pathology. Overall, these results highlight for the first time the role of Ser/Thr kinase-dependent KasB phosphorylation in regulating the later stages of mycolic acid elongation, with important consequences in terms of acid-fast staining and pathogenicity. 相似文献
994.
Kerstin Hünniger Teresa Lehnert Kristin Bieber Ronny Martin Marc Thilo Figge Oliver Kurzai 《PLoS computational biology》2014,10(2)
Candida albicans bloodstream infection is increasingly frequent and can result in disseminated candidiasis associated with high mortality rates. To analyze the innate immune response against C. albicans, fungal cells were added to human whole-blood samples. After inoculation, C. albicans started to filament and predominantly associate with neutrophils, whereas only a minority of fungal cells became attached to monocytes. While many parameters of host-pathogen interaction were accessible to direct experimental quantification in the whole-blood infection assay, others were not. To overcome these limitations, we generated a virtual infection model that allowed detailed and quantitative predictions on the dynamics of host-pathogen interaction. Experimental time-resolved data were simulated using a state-based modeling approach combined with the Monte Carlo method of simulated annealing to obtain quantitative predictions on a priori unknown transition rates and to identify the main axis of antifungal immunity. Results clearly demonstrated a predominant role of neutrophils, mediated by phagocytosis and intracellular killing as well as the release of antifungal effector molecules upon activation, resulting in extracellular fungicidal activity. Both mechanisms together account for almost of C. albicans killing, clearly proving that beside being present in larger numbers than other leukocytes, neutrophils functionally dominate the immune response against C. albicans in human blood. A fraction of C. albicans cells escaped phagocytosis and remained extracellular and viable for up to four hours. This immune escape was independent of filamentation and fungal activity and not linked to exhaustion or inactivation of innate immune cells. The occurrence of C. albicans cells being resistant against phagocytosis may account for the high proportion of dissemination in C. albicans bloodstream infection. Taken together, iterative experiment–model–experiment cycles allowed quantitative analyses of the interplay between host and pathogen in a complex environment like human blood. 相似文献
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996.
Volker U. Schwartze Sascha Winter Ekaterina Shelest Marina Marcet-Houben Fabian Horn Stefanie Wehner J?rg Linde Vito Valiante Michael Sammeth Konstantin Riege Minou Nowrousian Kerstin Kaerger Ilse D. Jacobsen Manja Marz Axel A. Brakhage Toni Gabaldón Sebastian B?cker Kerstin Voigt 《PLoS genetics》2014,10(8)
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999.
Anne Endmann Katharina Klünder Kerstin Kapp Oliver Riede Detlef Oswald Eduard G. Talman Matthias Schroff Christiane Kleuss Marcel H. J. Ruiters Christiane Juhls 《PloS one》2014,9(7)
Currently marketed vaccines against hepatitis B virus (HBV) based on the small (S) hepatitis B surface antigen (HBsAg) fail to induce a protective immune response in about 10% of vaccinees. DNA vaccination and the inclusion of PreS1 and PreS2 domains of HBsAg have been reported to represent feasible strategies to improve the efficacy of HBV vaccines. Here, we evaluated the immunogenicity of SAINT-18-formulated MIDGE-Th1 vectors encoding the S or the large (L) protein of HBsAg in mice and pigs. In both animal models, vectors encoding the secretion-competent S protein induced stronger humoral responses than vectors encoding the L protein, which was shown to be retained mainly intracellularly despite the presence of a heterologous secretion signal. In pigs, SAINT-18-formulated MIDGE-Th1 vectors encoding the S protein elicited an immune response of the same magnitude as the licensed protein vaccine Engerix-B, with S protein-specific antibody levels significantly higher than those considered protective in humans, and lasting for at least six months after the third immunization. Thus, our results provide not only the proof of concept for the SAINT-18-formulated MIDGE-Th1 vector approach but also confirm that with a cationic-lipid formulation, a DNA vaccine at a relatively low dose can elicit an immune response similar to a human dose of an aluminum hydroxide-adjuvanted protein vaccine in large animals. 相似文献