Protein misassembly leads to the formation of dysfunctional and toxic molecular species relating to neurodegeneration in Parkinson's disease and Alzheimer's disease. Here, we tailored a nanochaperone ...(αS‐nChap) for α‐synuclein to regulate its assembly. The αS‐nChap is capable of i) specifically recognizing α‐synuclein; ii) dynamically capturing and stabilizing monomeric α‐synuclein and retarding oligomerization; iii) tightly capturing oligomeric α‐synuclein to prevent fibrillization; and iv) transporting α‐synuclein oligomers to the lysosomal degradation system. The regulation of α‐synuclein assembly by αS‐nChap was studied in vitro. Moreover, the role of αS‐nChap preventing α‐synuclein pathology in cells and protecting neurons from apoptosis was investigated. The strategy of tailoring a nanochaperone to regulate aberrant assembly of pathogenic proteins provides important insights into protein misfolding diseases. We foresee that αS‐nChap has therapeutic value for Parkinson's disease.
A nanochaperone for α‐synuclein was designed and fabricated to prevent the misassembly of α‐synuclein. The nanochaperone, termed αS‐nChap, dynamically and transiently captures monomeric α‐synuclein and inhibits its oligomerization. Moreover, αS‐nChap tightly captures oligomeric α‐synuclein and inhibits its fibrillization.
Site‐specific modification of proteins with synthetic fluorescent tag effectively improves the resolution of imaging, and such a labeling method with negligible three‐dimensional structural ...perturbations and minimal impact on the biological functions of proteins is of high interest to dissect the high‐resolution activities of biomolecules in complex systems. To this end, several non‐emissive iridium(III) complexes Ir(C−N)2(H2O)2+OTF− (C−N denotes various cyclometalated ligands) were designed and synthesized. These complexes were tested for attaching a protein by coordinating to H/X (HisMet, HisHis, and HisCys) that are separated by i and i+4 in α‐helix. Replacement of the two labile water ligands in the iridium(III) complex by a protein HisHis pair increases the luminescent intensity up to over 100 folds. This labeling approach has been demonstrated in a highly specific and efficient manner in a number of proteins, and it is also feasible for labeling target proteins in cell lysates.
We developed a general method of site‐specific anchoring a luminescent Ir(III) moiety via coordination of protein sidechains. A number of Ir(III) complexes were tested for attachment on a protein by coordinating to H/X (HisMet, HisHis, and HisCys) that are separated by i and i+4 in α‐helix. Replacement of the two labile water ligands in the iridium(III) complex by protein H/H residues increases the luminescent intensity up to over one hundred folds. This labeling approach has been demonstrated in a highly specific and efficient manner in a number of proteins, and it is also feasible for labeling target proteins in complex systems.
Noble metal nanoparticles are promising catalysts in electrochemical reactions, while understanding the relationship between the structure and reactivity of the particles is important to achieve ...higher efficiency of electrocatalysis, and promote the development of single‐molecule electrochemistry. Electrogenerated chemiluminescence (ECL) was employed to image the catalytic oxidation of luminophore at single Au, Pt, and Au‐Pt Janus nanoparticles. Compared to the monometal nanoparticles, the Janus particle structure exhibited enhanced ECL intensity and stability, indicating better catalytic efficiency. On the basis of the experimental results and digital simulation, it was concluded that a concentration difference arose at the asymmetric bimetallic interface according to different heterogeneous electron‐transfer rate constants at Au and Pt. The fluid slip around the Janus particle enhanced local redox reactions and protected the particle surface from passivation.
Electrocatalytic oxidation of a luminophore at single Au, Pt, and Au‐Pt Janus nanoparticles was studied using electrogenerated chemiluminescence (ECL) microscopy. Compared to the monometal nanoparticles, the Janus particle structure exhibited enhanced ECL intensity and stability, indicating better catalytic efficiency.
Protein–protein coupling reactions under physiological conditions that do not impact the three‐dimensional structures of the proteins are in high demand. Owing to the combination of phenylsulfonyl ...and aldehyde groups in 5‐fluoro‐4‐(phenylsulfonyl)picolinaldehyde (FPPA), the fluorine substituent shows high reactivity toward free thiols. In FPPA, the fluorine is more reactive than phenylsulfonyl for free thiols. Thus the first quantitative nucleophilic substitution can be followed by selective substitution of phenylsulfonyl by an additional thiol or cyclization of aldehyde with a 1,2‐aminothiol molecule. The FPPA mediated protein–protein coupling proceeds efficiently under mild conditions, resulting in stable protein conjugates. This coupling method has negligible 3D structural perturbations on the target proteins, and it produces overall intact, nearly traceless, and native structural folds of proteins. It is highly suitable for reconstruction of proteins that are difficult to make and segmental isotopic labeling of multidomain proteins.
The different reactivities of the fluorine, aldehyde, and phenylsulfonyl groups in 5‐fluoro‐4‐(phenylsulfonyl)pincolinaldehyde (FPPA) toward free thiols make it possible to couple multiple proteins in distinct manners. A number of protein couplings mediated by FPPA have been demonstrated under mild conditions.
Joint spectral and spatial information should be fully exploited in order to achieve accurate classification results for hyperspectral images. In this paper, we propose an ensemble framework, which ...combines spectral and spatial information in different scales. The motivation of the proposed method derives from the basic idea: by integrating many individual learners, ensemble learning can achieve better generalization ability than a single learner. In the proposed work, the individual learners are obtained by joint spectral-spatial features generated from different scales. Specially, we develop two techniques to construct the ensemble model, namely, hierarchical guidance filtering (HGF) and matrix of spectral angle distance (mSAD). HGF and mSAD are combined via a weighted ensemble strategy. HGF is a hierarchical edge-preserving filtering operation, which could produce diverse sample sets. Meanwhile, in each hierarchy, a different spatial contextual information is extracted. With the increase of hierarchy, the pixels spectra tend smooth, while the spatial features are enhanced. Based on the outputs of HGF, a series of classifiers can be obtained. Subsequently, we define a low-rank matrix, mSAD, to measure the diversity among training samples in each hierarchy. Finally, an ensemble strategy is proposed using the obtained individual classifiers and mSAD. We term the proposed method as HiFi-We. Experiments are conducted on two popular data sets, Indian Pines and Pavia University, as well as a challenging hyperspectral data set used in 2014 Data Fusion Contest (GRSS_DFC_2014). An effectiveness analysis about the ensemble strategy is also displayed.
This paper concerns the generalized div‐curl‐gradient inequalities which control certain norms of the gradient of a vector field
u$$ \boldsymbol{u} $$ by using its divergence and curl in the domain ...and either the oblique trace
l·u$$ \boldsymbol{l}\cdotp \boldsymbol{u} $$ or the oblique component
l×u$$ \boldsymbol{l}\times \boldsymbol{u} $$ on the domain boundary, where
l$$ \boldsymbol{l} $$ is a nontangential vector field. These inequalities provide a priori estimates of the solutions of the div‐curl system with the boundary condition of prescribing either the oblique trace or the oblique component. We shall prove the inequalities and derive existence of the solutions under some geometric condition on the domain and on the vector field
l$$ \boldsymbol{l} $$.
This paper concerns the Maxwell–Stokes system with either curl-Robin boundary condition or mixed curl-Robin boundary condition. While the curl-Robin condition looks similar to the usual Robin ...condition for elliptic equations, the mixed curl-Robin condition involves the boundary value of the unknown potential and it arises naturally from the variational analysis in the space of vector fields with
L
2
boundary value. The weak solutions of both problems will be obtained by variational methods and compact operator methods. The mixed curl-Robin problem of nonlinear Maxwell–Stokes system will also be examined.
Aims. Acute kidney injury (AKI) can lead to chronic kidney disease (CKD), and macrophages play a key role in this process. The aim of this study was to discover the role of IκB kinase α (IKKα) in ...macrophages in the process of AKI-to-CKD transition. Main Methods. We crossed lyz2-Cre mice with IKKα-floxed mice to generate mice with IKKα ablation in macrophages (Mac IKKα-/-). A mouse renal ischemia/reperfusion injury (IRI) model was induced by clamping the renal artery for 45 minutes. Treated mice were evaluated for blood biochemistry, tissue histopathology, and fibrosis markers. Macrophages were isolated from the peritoneal cavity for coculturing with tubular epithelial cells (TECs) and flow cytometry analysis. Key Findings. We found that fibrosis and kidney function loss after IRI were significantly alleviated in Mac IKKα-/- mice compared with wild-type (WT) mice. The expression of fibrosis markers and the infiltration of M2 macrophages were decreased in the kidneys of Mac IKKα-/- mice after IRI. The in vitro experiment showed that the IRI TECs cocultured with IKKα-/- macrophages (KO MΦs) downregulated the fibrosis markers accompanied by a downregulation of Wnt/β-catenin signaling. Significance. These data support the hypothesis that IKKα is involved in mediating macrophage polarization and increasing the expression of fibrosis-promoting inflammatory factors in macrophages. Therefore, knockdown of IKKα in macrophages may be a potential method that can be used to alleviate the AKI-to-CKD transition after IRI.
A
bstract
In the framework of anti-de Sitter space/conformal field theory (AdS/CFT), we study the pole-skipping phenomenon of the holographic correlators of boundary operators. We explore the ...locations of the pole-skipping points case by case with the U(1)-gauged form models in the asymptotic AdS bulk of finite temperature. In general, in different cases all the points are located at the Matsubara frequencies with corresponding wave vectors dispersed in the momentum space, displaying different types of patterns. Specifically, in the massless cases with U(1) symmetry, the wave vectors of the pole-skipping points have a form-number dependence, and a trans-mode equivalence in the dual fields is found in correspondence with electromagnetic duality. In the massive cases with explicit symmetry breaking, the points degenerate to be independent of the form number. We expect in such kind of pole-skipping properties implications of distinctive physics in the chaotic systems. These properties are further examined by higher-order computation, which provides a more complete pole-skipping picture. Our near-horizon computation is verified with the double-trace method especially in the example of 2-form where there is dimension-dependent boundary divergence. We illustrate in these cases that the pole-skipping properties of the holographic correlators are determined by the IR physics, consistent with the ordinary cases in previous studies.
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