28 research outputs found

    Enhanced Sampling of Intrinsic Structural Heterogeneity of the BH3-Only Protein Binding Interface of Bcl-xL

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    Antiapoptotic Bcl-xL plays central roles in regulating programed cell death. Partial unfolding of Bcl-xL has been observed at the interface upon specific binding to the pro-apoptotic BH3-only protein PUMA, which in turn disrupts the interaction of Bcl-xL with tumor suppressor p53 and promotes apoptosis. Previous analysis of existing Bcl-xL structures and atomistic molecular dynamics (MD) simulations have suggested that substantial intrinsic structure heterogeneity exists at the BH3-only protein binding interface of Bcl-xL to facilitate its conformational transitions upon binding. In this study, enhanced sampling is applied to further characterize the interfacial conformations of unbound Bcl-xL in explicit solvent. Extensive replica exchange with solute tempering (REST) simulations, with a total accumulated time of 16 μs, were able to cover much wider conformational spaces for the interfacial region of Bcl-xL. The resulting structural ensembles are much better converged, with local and long-range structural features that are highly consistent with existing NMR data. These simulations further demonstrate that the BH3-only protein binding interface of Bcl-xL is intrinsically disordered and samples many rapidly interconverting conformations. Intriguingly, all previously observed conformers are well represented in the unbound structure ensemble. Such intrinsic structural heterogeneity and flexibility may be critical for Bcl-xL to undergo partial unfolding induced by PUMA binding, and likely provide a robust basis that allows Bcl-xL to respond sensitively to binding of various ligands in cellular signaling and regulation

    The forest plots of the comparation between IgAN group and control group.

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    <p>The forest plots of the comparation between IgAN group and control group.</p

    Photoluminescence Mechanism of DNA-Templated Silver Nanoclusters: Coupling between Surface Plasmon and Emitter and Sensing of Lysozyme

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    DNA-templated silver nanoclusters (DNA-AgNCs) have now been thrust into the limelight with their superior optical properties and potential biological applications. However, the origin of photoluminescence from DNA-AgNCs still remains unclear. In this work, DNA-AgNCs were synthesized and the photoluminescence properties as well as the biosensing applications of the designed DNA-AgNCs were investigated. The photoluminescence properties of the DNA-AgNCs were studied under three regions of excitation wavelength based on the UV–visible absorption spectra. It was deemed that the photoluminescence originated from coupling between the surface plasmon and the emitter in AgNCs when they were excited by visible light above 500 nm, and thus the emission wavelength varied with changing the excitation wavelength. The photoluminescence of the red-emitting-only AgNCs was the intrinsic fluorescence when excited from 200 to 400 nm, which was only related to the emitter; but for two components of blue- and red-emitting AgNCs, the emission wavelength varied with the excitation wavelength ranging from 300 to 360 nm, and the photoluminescence was a coupling between the surface plasmon and the emitter. The photoluminescence was only related to the surface plasmon when the AgNCs were excited from 400 to 500 nm. Four DNA probes were designed and each contained two parts: one part was the template used to synthesize AgNCs and it was same to all, and the other part was the lysozyme binding DNA (LBD) used to bind lysozyme and two kinds of LBD were studied. It was deemed that the difference in DNA bases, sequence, and secondary structure caused the synthesized DNA-AgNCs to be different in photoluminescence properties and sensing ability to lysozyme, and the sensing mechanism based on photoluminescence enhancement was also presented. This work explored the origin of photoluminescence and the sensing ability of DNA-AgNCs, and is hoped to make a better understanding of this kind of photoluminescence probe

    The forest plots of IgAN group and first-degree relatives group.

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    <p>The forest plots of IgAN group and first-degree relatives group.</p

    The forest plots of the comparation among IgAN group, HSPN group and controls.

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    <p>The forest plots of the comparation among IgAN group, HSPN group and controls.</p

    Aberrant IgA1 Glycosylation in IgA Nephropathy: A Systematic Review

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    <div><p>Objective</p><p>Galactose-deficient IgA1 was evaluated in patients with IgA nephropathy(IgAN) and controls in order to determine the predictive value of galactose-deficient IgA1 in cases of IgA nephropathy.</p><p>Methods</p><p>PubMed, EMBASE, Cochrane central register of controlled trials, CNKI, CBM disc, and VIP database were searched to identify eligible studies that evaluated a difference in aberrant IgA1 glycosylation in IgAN patients compared with controls. A meta-analysis was conducted to evaluate the impact of galactose-deficient IgA1(Gd-IgA1) levels in different groups.</p><p>Results</p><p>A total of 22 studies (n = 1657) met inclusion criteria. The mean Newcastle-Ottawa Scale (NOS) score was 7.2 and ranged from 6 to 8. The standard mean difference(SMD) in the meta-analysis of 20 studies of the level of Gd-IgA1 in the serum and/or supernatant of cultured cells was higher in the IgAN group compared with healthy controls as well as in those with other renal diseases (SMD = 1.76, 95% CI = 1.18–2.34, P<0.00001; SMD = 1.05, 95% CI = 0.05–2.04, P = 0.04). The data synthesis suggested that IgAN patients had similar levels of serum Gd-IgA1, with no significant differences, compared with first-degree relatives and Henoch-Schonlein purpura nephritis (HSPN) patients (MD = 0.04, 95% CI = 0.00–0.08, P = 0.05; MD = -46.03, 95% CI = -217.70–125.64, P = 0.60). In addition, the combined MD of 5 studies indicated that there were no significant differences in Gd-IgA1 levels among patients with varying severities of IgAN (MD = 0.02, 95% CI = -0.02–0.05, P = 0.28).</p><p>Conclusions</p><p>The pooled evidence suggests that the level of Gd-IgA1 in the serum or supernatant of cultured cells from peripheral blood or tonsils may be a useful biomarker for predicting IgA nephropathy, though the level of Gd-IgA1 was not significantly associated with disease severity.</p></div

    Translocation Thermodynamics of Linear and Cyclic Nonaarginine into Model DPPC Bilayer via Coarse-Grained Molecular Dynamics Simulation: Implications of Pore Formation and Nonadditivity

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    Structural mechanisms and underlying thermodynamic determinants of efficient internalization of charged cationic peptides (cell-penetrating peptides, CPPs) such as TAT, polyarginine, and their variants, into cells, cellular constructs, and model membrane/lipid bilayers (large and giant unilamellar or multilamelar vesicles) continue to garner significant attention. Two widely held views on the translocation mechanism center on endocytotic and nonendocytotic (diffusive) processes. Espousing the view of a purely diffusive internalization process (supported by recent experimental evidence, [Säälik, P.; et al. <i>J. Controlled Release</i> <b>2011</b>, <i>153</i>, 117–125]), we consider the underlying free energetics of the translocation of a nonaarginine peptide (Arg<sub>9</sub>) into a model DPPC bilayer. In the case of the Arg<sub>9</sub> cationic peptide, recent experiments indicate a higher internalization efficiency of the cyclic structure (cyclic Arg<sub>9</sub>) relative to the linear conformer. Furthermore, recent all-atom resolution molecular dynamics simulations of cyclic Arg<sub>9</sub> [Huang, K.; et al. <i>Biophys. J.</i>, <b>2013</b>, <i>104</i>, 412–420] suggested a critical stabilizing role of water- and lipid-constituted pores that form within the bilayer as the charged Arg<sub>9</sub> translocates deep into the bilayer center. Herein, we use umbrella sampling molecular dynamics simulations with coarse-grained Martini lipids, polarizable coarse-grained water, and peptide to explore the dependence of translocation free energetics on peptide structure and conformation via calculation of potentials of mean force along preselected reaction paths allowing and preventing membrane deformations that lead to pore formation. Within the context of the coarse-grained force fields we employ, we observe significant barriers for Arg<sub>9</sub> translocation from bulk aqueous solution to bilayer center. Moreover, we do not find free-energy minima in the headgroup–water interfacial region, as observed in simulations using all-atom force fields. The pore-forming paths systematically predict lower free-energy barriers (ca. 90 kJ/mol lower) than the non pore-forming paths, again consistent with all-atom force field simulations. The current force field suggests no preference for the more compact or covalently cyclic structures upon entering the bilayer. Decomposition of the PMF into the system’s components indicates that the dominant stabilizing contribution along the pore-forming path originates from the membrane as both layers of it deformed due to the formation of pore. Furthermore, our analysis revealed that although there is significant entropic stabilization arising from the enhanced configurational entropy exposing more states as the peptide moves through the bilayer, the enthalpic loss (as predicted by the interactions of this coarse-grained model) far outweighs any former stabilization, thus leading to significant barrier to translocation. Finally, we observe reduction in the translocation free-energy barrier for a second Arg<sub>9</sub> entering the bilayer in the presence of an initial peptide restrained at the center, again, in qualitative agreement with all-atom force fields

    The forest plots of comparison among variable grades of IgAN severity.

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    <p>The forest plots of comparison among variable grades of IgAN severity.</p
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