Background and Purpose: Oligomeric Aβ1-42 (oAβ42) exhibits agonist-like action at human α7- and α7β2-nicotinic receptors (collectively, α7*-nAChR). Aβ1-42 and an N-terminal Aβ peptide fragment (N-Aβ fragment: Aβ1-15/16) have been shown to modulate presynaptic Ca2+ and enhance hippocampus-based synaptic plasticity via α7* nAChR. Both the N-Aβ fragment and its essential core sequence, the N-Aβcore hexapeptide (Aβ10-15), protect against Aβ-associated synapto- and neurotoxicity, also involving nAChR. Here, we investigated how oAβ42, the N-Aβ fragment and N-Aβcore regulate the functional activity of α7*-nAChRs. Experimental approach: Single-channel patch clamp recordings measured the impact of ACh, oAβ42, the N-Aβ fragment, and the N-Aβcore on the function of concatenated, human α7- and α7β2-containing nAChR expressed in nAChR-null SH-EP1 cells. Molecular dynamics simulations identified potential sites of interaction between the N-Aβ fragment and the orthosteric α7*-nAChR binding interfaces. Key Results: Relative to the effects of ACh alone, oAβ42 preferentially enhanced α7β2-nAChR open probability and open-dwell times. Co-application with the N-Aβcore neutralized these effects. Further, we demonstrate that the N-Aβ fragment alone, or in combination with ACh or oAβ42, resulted in selective enhancement of α7-nAChR single-channel open probability and open-dwell times (compared to ACh or oAβ42). Conclusions and Implications: Our findings show the functional diversity of Aβ peptides in regulating α7*-nAChR function, with implications for a wide range of nAChR-mediated functions in AD. Single-channel recordings of the differential effects of oAβ42, N-Aβ fragment and/or N-Aβcore on α7*-nAChR isoform function revealed the complexities of their interactions with α7*-nAChR, with new insights into the neuroprotective actions of these N-Aβ-derived peptides.
The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents a public health crisis, and the vaccines that can induce highly potent neutralizing antibodies are essential for ending the pandemic. The spike (S) protein on the viral envelope mediates human angiotensin-converting enzyme 2 (ACE2) binding and thus is the target of a variety of neutralizing antibodies. In this work, we built various S trimer-antibody complex structures on the basis of the fully glycosylated S protein models described in our previous work, and performed all-atom molecular dynamics simulations to get insight into the structural dynamics and interactions between S protein and antibodies. Investigation of the residues critical for S-antibody binding allows us to predict the potential influence of mutations in SARS-CoV-2 variants. Comparison of the glycan conformations between S-only and S-antibody systems reveals the roles of glycans in S-antibody binding. In addition, we explored the antibody binding modes, and the influences of antibody on the motion of S protein receptor binding domains. Overall, our analyses provide a better understanding of S-antibody interactions, and the simulation-based S-antibody interaction maps could be used to predict the influences of S mutation on S-antibody interactions, which will be useful for the development of vaccine and antibody-based therapy.
Rational drug design involves a task of finding ligands that would bind to a specific target protein. This work presents CHARMM-GUI Ligand Designer that is an intuitive and interactive web-based tool to design virtual ligands that match the shape and chemical features of a given protein binding site. Ligand Designer provides ligand modification capabilities with 3D visualization that allow researchers to modify and redesign virtual ligands while viewing how the protein–ligand interactions are affected. Virtual ligands can also be parameterized for further molecular dynamics (MD) simulations and free energy calculations. Using 8 targets from 8 different protein classes in the directory of useful decoys, enhanced (DUD-E) data set, we show that Ligand Designer can produce similar ligands to the known active ligands in the crystal structures. Ligand Designer also produces stable protein–ligand complex structures when tested using short MD simulations. We expect that Ligand Designer can be a useful and user-friendly tool to design small molecules in any given potential ligand binding site on a protein of interest.
The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents a public health crisis, and the vaccines that can induce highly potent neutralizing antibodies are essential for ending the pandemic. The spike (S) protein on the viral envelope mediates human angiotensin-converting enzyme 2 binding and thus is the target of a variety of neutralizing antibodies. In this work, we built various S trimer–antibody complex structures on the basis of the fully glycosylated S protein models described in our previous work and performed all-atom molecular dynamics simulations to gain insight into the structural dynamics and interactions between S protein and antibodies. Investigation of the residues critical for S–antibody binding allows us to predict the potential influence of mutations in SARS-CoV-2 variants. Comparison of the glycan conformations between S-only and S–antibody systems reveals the roles of glycans in S–antibody binding. In addition, we explored the antibody binding modes and the influences of antibody on the motion of S protein receptor binding domains. Overall, our analyses provide a better understanding of S–antibody interactions, and the simulation-based S–antibody interaction maps could be used to predict the influences of S mutation on S–antibody interactions, which will be useful for the development of vaccine and antibody-based therapy.
Portfolio assessment is valued because of its function of promoting student development and teaching improvement,but lower reliability and validity have limited the use of portfolio assessment in teaching assessment.This study carried out an experimental research on the rater reliability of portfolio assessment.Four raters scored 152 portfolios twice.Various statistical methods were used to evaluate the inter-rater reliability.The results showed the scoring has a high relativity,a medium-low consistency and a certain stability.The rater reliability of multi-rater scoring of the overall level of the portfolio is the highest.In this research,generalizability coefficient and dependability coefficient of the scoring of the overall level of the portfolios by the three raters are all above 0.80.
In the recent years more and more people have begun to edit video files, as technologies are becoming more sophisticated and affordable. Web 2.0 has raised tagging functionality to a growing number of websites such as Flickr and YouTube. However, these services only provide basic video annotation support. In comparison to those well-known services there are many research efforts towards video semantization tools. These tools provide highly precise annotation functionality based on metadata standards such as MPEG-7, but tend to exhibit very complex user interfaces. In this paper we present the design, implementation and evaluation of SeViAnno, an MPEG-7 based interactive semantic video annotation Web platform with the main objective to find a well-balanced trade-off between a simple user interface and video semantization complexity.
Objective: Some defects in the development and revision of scales were analyzed and discussed. Methods: 410 scales were selected from published Chinese journals in the China National Knowledge Infrastruct(CNKI). Results: ① For 365 self -made scales (77.5% ), the goals and/or dimensions of scales were not clear before construction; ② The distribution of samples were limited comparatively; ③The results of item analysis were reported only in few articles and there were problems of methodology; ④The medians of internal consistence of the full scales were 0.872 (α coefficient) and 0.861 (split-half coefficient), and the medians of internal consistence of the average facets were 0.774 (both α and split-half coefficient). The stabilities of scales and the average facets were 0.810 and 0.745, but half of the stabilities were not reported. ⑤The method of factor analysis was used inappropriately in some articles. The criterion-related validities were not reported in 40% articles.
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