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41.
Arne Lindqvist Anneloes Mensinga Wytse Bruinsma Olaf Voets Onno Kranenburg René H Medema 《The EMBO journal》2009,28(20):3196-3206
Activation of the DNA damage checkpoint causes a cell‐cycle arrest through inhibition of cyclin‐dependent kinases (cdks). To successfully recover from the arrest, a cell should somehow be maintained in its proper cell‐cycle phase. This problem is particularly eminent when a cell arrests in G2, as cdk activity is important to establish a G2 state. Here, we identify the phosphatase Wip1 (PPM1D) as a factor that maintains a cell competent for cell‐cycle re‐entry during an ongoing DNA damage response in G2. We show that Wip1 function is required throughout the arrest, and that Wip1 acts by antagonizing p53‐dependent repression of crucial mitotic inducers, such as Cyclin B and Plk1. Our data show that the primary function of Wip1 is to retain cellular competence to divide, rather than to silence the checkpoint to promote recovery. Our findings uncover Wip1 as a first in class recovery competence gene, and suggest that the principal function of Wip1 in cellular transformation is to retain proliferative capacity in the face of oncogene‐induced stress. 相似文献
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Munc18-1 promotes large dense-core vesicle docking. 总被引:21,自引:0,他引:21
T Voets R F Toonen E C Brian H de Wit T Moser J Rettig T C Südhof E Neher M Verhage 《Neuron》2001,31(4):581-591
Secretory vesicles dock at the plasma membrane before Ca(2+) triggers their exocytosis. Exocytosis requires the assembly of SNARE complexes formed by the vesicle protein Synaptobrevin and the membrane proteins Syntaxin-1 and SNAP-25. We analyzed the role of Munc18-1, a cytosolic binding partner of Syntaxin-1, in large dense-core vesicle (LDCV) secretion. Calcium-dependent LDCV exocytosis was reduced 10-fold in mouse chromaffin cells lacking Munc18-1, but the kinetic properties of the remaining release, including single fusion events, were not different from controls. Concomitantly, mutant cells displayed a 10-fold reduction in morphologically docked LDCVs. Moreover, acute overexpression of Munc18-1 in bovine chromaffin cells increased the amount of releasable vesicles and accelerated vesicle supply. We conclude that Munc18-1 functions upstream of SNARE complex formation and promotes LDCV docking. 相似文献
45.
Ines Lesniak Ilja Heckmann Mathias Franz Alex D. Greenwood Emanuel Heitlinger Heribert Hofer Oliver Krone 《Ecology and evolution》2018,8(4):2160-2170
The recent recolonization of Central Europe by the European gray wolf (Canis lupus) provides an opportunity to study the dynamics of parasite transmission for cases when a definitive host returns after a phase of local extinction. We investigated whether a newly established wolf population increased the prevalence of those parasites in ungulate intermediate hosts representing wolf prey, whether some parasite species are particularly well adapted to wolves, and the potential basis for such adaptations. We recorded Sarcocystis species richness in wolves and Sarcocystis prevalence in ungulates harvested in study sites with and without permanent wolf presence in Germany using microscopy and DNA metabarcoding. Sarcocystis prevalence in red deer (Cervus elaphus) was significantly higher in wolf areas (79.7%) than in control areas (26.3%) but not in roe deer (Capreolus capreolus) (97.2% vs. 90.4%) or wild boar (Sus scrofa) (82.8% vs. 64.9%). Of 11 Sarcocystis species, Sarcocystis taeniata and Sarcocystis grueneri occurred more often in wolves than expected from the Sarcocystis infection patterns of ungulate prey. Both Sarcocystis species showed a higher increase in prevalence in ungulates in wolf areas than other Sarcocystis species, suggesting that they are particularly well adapted to wolves, and are examples of “wolf specialists”. Sarcocystis species richness in wolves was significantly higher in pups than in adults. “Wolf specialists” persisted during wolf maturation. The results of this study demonstrate that (1) predator–prey interactions influence parasite prevalence, if both predator and prey are part of the parasite life cycle, (2) mesopredators do not necessarily replace the apex predator in parasite transmission dynamics for particular parasites of which the apex predator is the definitive host, even if meso‐ and apex predators were from the same taxonomic family (here: Canidae, e.g., red foxes Vulpes vulpes), and (3) age‐dependent immune maturation contributes to the control of protozoan infection in wolves. 相似文献
46.
Denise Sa?enroth Antje Meyer Bastian Salewsky Martin Kroh Kristina Norman Elisabeth Steinhagen-Thiessen Ilja Demuth 《PloS one》2015,10(12)
Physical activity and sports have repeatedly been reported to be associated with telomere length. We studied the association of different types of sports across different stages of life on relative leukocyte telomere length (rLTL) in advanced age.815 participants (397 men) from the Berlin Aging Study II aged over 61 years were included in the analysis. rLTL was measured by real time PCR and physical activity was determined retrospectively by questionnaire, assessing type and duration of sports in the past as well as currently. Five separate multiple linear regression models adjusted for various control variables were performed. 67.3% of participants exercised currently, whereas 19.4% performed sports only between the age of 20 and 30. rLTL was higher in subjects who stated to exercise currently (N = 456), and in subjects who engaged in endurance (N = 138) or intensive activity sports (N = 32). Current physical activity was positively associated with rLTL in the risk factor adjusted regression model (β = 0.26, p < 0.001) and practicing sports for a minimum of 10 years preceding the assessment had a significant effect on rLTL (β = 0.39, p = 0.011). The highest impact was seen for intensive activity sports (β = 0.79, p < 0.001) and physical activity since at least 42 years (β = 0.47, p = 0.001). However, physical activity only between 20 and 30 years of age did not affect rLTL in old age when compared to no sports at all (β = -0.16, p = 0.21). Physical activity is clearly associated with longer rLTL. The effect is seen with longer periods of physical activity (at least 10 years), with intensive sports activities having the greatest impact on rLTL. Our data suggest that regular physical activity for at least 10 years is necessary to achieve a sustained effect on rLTL. 相似文献
47.
A Belonostomus tenuirostris (Agassiz, 1833) from Late Kimmeridgian (Late Jurassic) of Kelheim (Solnhofen area; Bavaria, southern Germany) that was preserved with three prey fishes in its digestive tract is described. Two of the prey fishes can be assigned to cf. Leptolepides (Orthogonikleithridae), whereas the third possibly represents a juvenile Caturus sp. (Caturidae). This is the first record of a Belonostomus with several prey animals, and the first evidence of a caturid predated by an aspidorhynchid. 相似文献
48.
Nilius B Mahieu F Prenen J Janssens A Owsianik G Vennekens R Voets T 《The EMBO journal》2006,25(3):467-478
Transient receptor potential (TRP) channel, melastatin subfamily (TRPM)4 is a Ca2+-activated monovalent cation channel that depolarizes the plasma membrane and thereby modulates Ca2+ influx through Ca2+-permeable pathways. A typical feature of TRPM4 is its rapid desensitization to intracellular Ca2+ ([Ca2+]i). Here we show that phosphatidylinositol 4,5-biphosphate (PIP2) counteracts desensitization to [Ca2+]i in inside-out patches and rundown of TRPM4 currents in whole-cell patch-clamp experiments. PIP2 shifted the voltage dependence of TRPM4 activation towards negative potentials and increased the channel's Ca2+ sensitivity 100-fold. Conversely, activation of the phospholipase C (PLC)-coupled M1 muscarinic receptor or pharmacological depletion of cellular PIP2 potently inhibited currents through TRPM4. Neutralization of basic residues in a C-terminal pleckstrin homology (PH) domain accelerated TRPM4 current desensitization and strongly attenuated the effect of PIP2, whereas mutations to the C-terminal TRP box and TRP domain had no effect on the PIP2 sensitivity. Our data demonstrate that PIP2 is a strong positive modulator of TRPM4, and implicate the C-terminal PH domain in PIP2 action. PLC-mediated PIP2 breakdown may constitute a physiologically important brake on TRPM4 activity. 相似文献
49.
Optimization of human immunodeficiency virus type 1 envelope glycoproteins with V1/V2 deleted, using virus evolution
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Bontjer I Land A Eggink D Verkade E Tuin K Baldwin C Pollakis G Paxton WA Braakman I Berkhout B Sanders RW 《Journal of virology》2009,83(1):368-383
The human immunodeficiency virus type 1 envelope glycoprotein (Env) complex is the principal focus of neutralizing antibody-based vaccines. The functional Env complex is a trimer consisting of six individual subunits: three gp120 molecules and three gp41 molecules. The individual subunits have proven unsuccessful as vaccines presumably because they do not resemble the functional Env complex. Variable domains and carbohydrates shield vulnerable neutralization epitopes on the functional Env complex. The deletion of variable loops has been shown to improve gp120's immunogenicity; however, problems have been encountered when introducing such modifications in stabilized Env trimer constructs. To address these issues, we have created a set of V1/V2 and V3 loop deletion variants in the context of complete virus to allow optimization by forced virus evolution. Compensatory second-site substitutions included the addition and/or removal of specific carbohydrates, changes in the disulfide-bonded architecture of the V1/V2 stem, the replacement of hydrophobic residues by hydrophilic and charged residues, and changes in distal parts of gp120 and gp41. These viruses displayed increased sensitivity to neutralizing antibodies, demonstrating the improved exposure of conserved domains. The results show that we can select for functionally improved Env variants with loop deletions through forced virus evolution. Selected evolved Env variants were transferred to stabilized Env trimer constructs and were shown to improve trimer expression and secretion. Based on these findings, we can make recommendations on how to delete the V1/V2 domain from recombinant Env trimers for vaccine and X-ray crystallography studies. In general, virus evolution may provide a powerful tool to optimize Env vaccine antigens. 相似文献
50.
Anna Melchers Lars St?ckl Janina Radszewski Marco Anders Harald Krenzlin Candy Kalischke Regina Scholz Andreas Jordan Grit Nebrich Joachim Klose Karl Sperling Martin Digweed Ilja Demuth 《PloS one》2009,4(5)