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1.
Jung Mi Lim Kyung S. Lee Hyun Ae Woo Dongmin Kang Sue Goo Rhee 《The Journal of cell biology》2015,210(1):935-945
Proteins associated with the centrosome play key roles in mitotic progression in mammalian cells. The activity of Cdk1-opposing phosphatases at the centrosome must be inhibited during early mitosis to prevent premature dephosphorylation of Cdh1—an activator of the ubiquitin ligase anaphase-promoting complex/cyclosome—and the consequent premature degradation of mitotic activators. In this paper, we show that reversible oxidative inactivation of centrosome-bound protein phosphatases such as Cdc14B by H2O2 is likely responsible for this inhibition. The intracellular concentration of H2O2 increases as the cell cycle progresses. Whereas the centrosome is shielded from H2O2 through its association with the H2O2-eliminating enzyme peroxiredoxin I (PrxI) during interphase, the centrosome-associated PrxI is selectively inactivated through phosphorylation by Cdk1 during early mitosis, thereby exposing the centrosome to H2O2 and facilitating inactivation of centrosome-bound phosphatases. Dephosphorylation of PrxI by okadaic acid–sensitive phosphatases during late mitosis again shields the centrosome from H2O2 and thereby allows the reactivation of Cdk1-opposing phosphatases at the organelle. 相似文献
2.
Soohyun Ahn Johan Lim Myunghee Cho Paik Ralph L. Sacco Mitchell S. Elkind 《Biometrical journal. Biometrische Zeitschrift》2018,60(4):797-814
In cohort studies the outcome is often time to a particular event, and subjects are followed at regular intervals. Periodic visits may also monitor a secondary irreversible event influencing the event of primary interest, and a significant proportion of subjects develop the secondary event over the period of follow‐up. The status of the secondary event serves as a time‐varying covariate, but is recorded only at the times of the scheduled visits, generating incomplete time‐varying covariates. While information on a typical time‐varying covariate is missing for entire follow‐up period except the visiting times, the status of the secondary event are unavailable only between visits where the status has changed, thus interval‐censored. One may view interval‐censored covariate of the secondary event status as missing time‐varying covariates, yet missingness is partial since partial information is provided throughout the follow‐up period. Current practice of using the latest observed status produces biased estimators, and the existing missing covariate techniques cannot accommodate the special feature of missingness due to interval censoring. To handle interval‐censored covariates in the Cox proportional hazards model, we propose an available‐data estimator, a doubly robust‐type estimator as well as the maximum likelihood estimator via EM algorithm and present their asymptotic properties. We also present practical approaches that are valid. We demonstrate the proposed methods using our motivating example from the Northern Manhattan Study. 相似文献
3.
Nur Syafiqah Abdul Ghani Roghayeh Abedi Karjiban Mahiran Basri Nur Hana Faujan Wui Zhuan Lim 《International journal of peptide research and therapeutics》2017,23(3):393-407
Alzheimer’s disease (AD) is a neurodegenerative disorder caused by overproduction and accumulation of amyloid beta-peptide (Aβ). The hallmarks associated with this AD are the presence of Aβ plaques between the nerve cell in the brain which leading to synaptic loss in memory. The amyloid plaques contain of transition metals like zinc, copper and iron. In a healthy brain, the metal ions are present in balance concentration. High concentrations of Zn are normally released during neurotransmission process. The release of Zn might cause the aggregation of Aβ leading to AD. Amyloid-β1–42 is the main type of Aβ in amyloid plaque. There still have limited explanation on how Aβ1–42 interaction with Zn metal, as well as the effect of Zn metal on the Aβ structure in different solvents in atomic detail. Therefore, we investigated the structural changes of Aβ1–42 in water (Aβ-H2O) and the mixed hexafluoroisopropanol (HFIP) with water (Aβ-HFIP/H2O). The mixed solvent consisted of hexafluoroisopropanol (HFIP) and water was used with the ratio of HFIP:H2O (80:20). The effect of zinc ion was also examined for the interaction of Aβ peptide with zinc in water (Aβ-Zn-H2O) and mixed solvent (Aβ-Zn-HFIP/H2O) using all atom level molecular dynamics (MD) calculations for 1 μs. We found that Aβ-Zn-HFIP/H2O contained more α-helix compared to Aβ-HFIP/H2O while Aβ-H2O and Aβ-Zn-H2O produced well-dissolved structure and they contained more β-sheets. β-turns are possible to bind with the receptor proteins and may induce the aggregation process in AD. Thus, Aβ-H2O and Aβ-Zn-H2O have higher possibility leading to AD compared to Aβ-Zn-HFIP/H2O and Aβ-HFIP/H2O models. 相似文献
4.
Mutations affecting the catalytic activity of Bacillus cereus 5/B/6 beta-lactamase II 总被引:2,自引:0,他引:2
Random in vitro mutagenesis of a cloned Bacillus cereus 5/B/6 beta-lactamase II gene was used to select defective genes unable to confer ampicillin or cephalosporin C resistance to Escherichia coli. DNA sequencing of mutant genes identified histidine at position 28 as important to beta-lactamase II function. In addition, the isolation of six identical frameshift mutants established that the carboxyl-terminal end of beta-lactamase II is critical for enzyme function. Random mutagenesis also revealed that His88 (implicated previously as one of 4 residues acting as a zinc ligand) is crucial to enzymatic activity and that a glycine to glutamic acid substitution at position 148 produced a defective beta-lactamase. Oligonucleotide mutagenesis directed at Glu37 and Glu212 suggests that these residues are inconsequential to enzyme function but that histidine at position 28 may be involved in substrate binding or recognition. 相似文献
5.
6.
Hee Jung Lim Jusong Kim Chang-Hwan Park Sang A. Lee Man Ryul Lee Kye-Seong Kim Jaesang Kim Yun Soo Bae 《The Journal of biological chemistry》2016,291(2):752-761
We have previously reported that Ahnak-mediated TGFβ signaling leads to down-regulation of c-Myc expression. Here, we show that inhibition of Ahnak can promote generation of induced pluripotent stem cells (iPSC) via up-regulation of endogenous c-Myc. Consistent with the c-Myc inhibitory role of Ahnak, mouse embryonic fibroblasts from Ahnak-deficient mouse (Ahnak−/− MEF) show an increased level of c-Myc expression compared with wild type MEF. Generation of iPSC with just three of the four Yamanaka factors, Oct4, Sox2, and Klf4 (hereafter 3F), was significantly enhanced in Ahnak−/− MEF. Similar results were obtained when Ahnak-specific shRNA was applied to wild type MEF. Of note, expressionof Ahnak was significantly induced during the formation of embryoid bodies from embryonic stem cells, suggesting that Ahnak-mediated c-Myc inhibition is involved in embryoid body formation and the initial differentiation of pluripotent stem cells. The iPSC from 3F-infected Ahnak−/− MEF cells (Ahnak−/−-iPSC-3F) showed expression of all stem cell markers examined and the capability to form three primary germ layers. Moreover, injection of Ahnak−/−-iPSC-3F into athymic nude mice led to development of teratoma containing tissues from all three primary germ layers, indicating that iPSC from Ahnak−/− MEF are bona fide pluripotent stem cells. Taken together, these data provide evidence for a new role for Ahnak in cell fate determination during development and suggest that manipulation of Ahnak and the associated signaling pathway may provide a means to regulate iPSC generation. 相似文献
7.
Bo Ram Kim Ji-Young Park Hyung Jae Jeong Hyung-Jun Kwon Su-Jin Park In-Chul Lee 《Journal of enzyme inhibition and medicinal chemistry》2018,33(1):1256-1265
Sialidases are key virulence factors that remove sialic acid from the host cell surface glycan, unmasking receptors that facilitate bacterial adherence and colonisation. In this study, we developed potential agents for treating bacterial infections caused by Streptococcus pneumoniae Nan A that inhibit bacterial sialidase using Turmeric and curcumin analogues. Design, synthesis, and structure analysis relationship (SAR) studies have been also described. Evaluation of the synthesised derivatives demonstrated that compound 5e was the most potent inhibitor of S. pneumoniae sialidase (IC50?=?0.2?±?0.1?µM). This compound exhibited a 3.0-fold improvement in inhibitory activity over that of curcumin and displayed competitive inhibition. These results warrant further studies confirming the antipneumococcal activity 5e and indicated that curcumin derivatives could be potentially used to treat sepsis by bacterial infections. 相似文献
8.
Contribution of autophagy and regulation of related proteins to the degeneration of retinal pigment epithelium (RPE) in age-related macular degeneration (AMD) remain unknown. We report that upregulation of KRT8 (keratin 8) as well as its phosphorylation are accompanied with autophagy and attenuated with the inhibition of autophagy in RPE cells under oxidative stress. KRT8 appears to have a dual role in RPE pathophysiology. While increased expression of KRT8 following autophagy provides a cytoprotective role in RPE, phosphorylation of KRT8 induces pathologic epithelial-mesenchymal transition (EMT) of RPE cells under oxidative stress, which is mediated by MAPK1/ERK2 (mitogen-activated protein kinase 1) and MAPK3/ERK1. Inhibition of autophagy further promotes EMT, which can be reversed by inhibition of MAPK. Thus, regulated enhancement of autophagy with concurrent increased expression of KRT8 and the inhibition of KRT8 phosphorylation serve to inhibit oxidative stress-induced EMT of RPE cells as well as to prevent cell death, suggesting that pharmacological manipulation of KRT8 upregulation through autophagy with combined inhibition of the MAPK1/3 pathway may be attractive therapeutic strategies for the treatment of AMD. 相似文献
9.
10.
A molecular phylogeny of New World emballonurid bats based on parsimony and Bayesian analyses of loci from the three different
nuclear genetic transmission pathways in mammals (autosomal, X, and Y chromosomes) is well supported and independently corroborated by each individual gene tree. This is in contrast to a single
most parsimonious but poorly supported tree based on morphological data, which has only one intergeneric or higher relationship
shared with the molecular phylogeny. Combining the morphological and molecular data partitions results in a tree similar to
the molecular tree suggesting a high degree of homoplasy and low phylogenetic signal in the morphological data set. Behavioral
data are largely incomplete and likewise produce a poorly resolved tree. Nonetheless, patterns of evolution in morphology
and behavior can be investigated by using the molecular tree as a phylogenetic framework. Character optimization of the appearance
of dorsal fur and preferred roosting sites maps consistently and are correlated on the phylogeny. This suggests an association
of camouflage for bats with unusual appearance (two dorsal stripes in Rhynchonycteris and Saccopteryx, or pale fur in Cyttarops and Diclidurus) and roosting in exposed sites (tree trunks or under palm leaves). In contrast, the ancestral states for Old and New World
emballonurids are typically uniform brown or black, and they usually roost in sheltered roosts such as caves and tree hollows.
Emballonuridae is the only family of bats that has a sac-like structure in the wing propatagium, which is found in four New
World genera. Mapping the wing sac character states onto the phylogeny indicates that wing sacs evolved independently within
each genus and that there may be a phylogenetic predisposition for this structure. Ear orientation maps relatively consistently
on the molecular phylogeny and is correlated to echolocation call parameters and foraging behavior, suggesting a phylogenetic
basis for these character systems. 相似文献