Xiaoyan Zhang

DNA base pairing has been used for many years to direct the arrangement of inorganic nanocrystals into small groupings and arrays with tailored optical and electrical properties. The control of DNA-mediated assembly depends crucially on a better understanding of three-dimensional structure of DNA-nanocrystal-hybridized building blocks. Existing techniques do not allow for structural determination of these flexible and heterogeneous samples. Here we report cryo-electron microscopy and negative-staining electron tomography approaches to image, and three-dimensionally reconstruct a single DNA-nanogold conjugate, an 84-bp double-stranded DNA with two 5-nm nanogold particles for potential substrates in plasmon-coupling experiments. By individual-particle electron tomography reconstruction, we obtain 14 density maps at ~ 2-nm resolution. Using these maps as constraints, we derive 14 conformations of dsDNA by molecular dynamics simulations. The conformational variation is consistent with that from liquid solution, suggesting that individual-particle electron tomography could be an expected approach to study DNA-assembling and flexible protein structure and dynamics.

Cholesteryl ester transfer protein mediates cholesteryl ester transfer from the atheroprotective high density lipoprotein cholesterol to the atherogenic low density lipoprotein cholesterol. In the past decade, this property has driven the development of CETP inhibitors, which have been evaluated in large scale clinical trials for treating cardiovascular diseases. Despite the pharmacological interest, little is known about the fundamental mechanism of CETP in CE transfer. Recent electron microscopy experiments have suggested a tunnel mechanism, and molecular dynamics simulations have shown that the flexible N-terminal distal end of CETP penetrates into the HDL surface and takes up a CE molecule through an open pore. However, it is not known whether a CE molecule can completely transfer through an entire CETP molecule. Here, we used all-atom molecular dynamics simulations to evaluate this possibility. The results showed that a hydrophobic tunnel inside CETP is sufficient to allow a CE molecule to completely transfer through the entire CETP within a predicted transfer time and at a rate comparable with those obtained through physiological measurements. Analyses of the detailed interactions revealed several residues that might be critical for CETP function, which may provide important clues for the effective development of CETP inhibitors and treatment of cardiovascular diseases.

Commonly used methods for determining protein structure, including X-ray crystallography and single-particle reconstruction, often provide a single and unique three-dimensional structure. However, in these methods, the protein dynamics and flexibility/fluctuation remain mostly unknown. Here, we utilized advances in electron tomography to study the antibody flexibility and fluctuation through structural determination of individual antibody particles rather than averaging multiple antibody particles together. Through individual-particle electron tomography 3D reconstruction from negatively-stained ET images, we obtained 120 ab-initio 3D density maps at an intermediate resolution from 120 individual IgG1 antibody particles. Using these maps as a constraint, we derived 120 conformations of the antibody via structural flexible docking of the crystal structure to these maps by targeted molecular dynamics simulations. Statistical analysis of the various conformations disclosed the antibody 3D conformational flexibility through the distribution of its domain distances and orientations. This blueprint approach, if extended to other flexible proteins, may serve as a useful methodology towards understanding protein dynamics and functions.

Objectives: The aim of the current study was to differentiate between neural activity that represents neural anomalies that are responsible for persistent developmental stuttering from the activity that is a result of compensating for stuttering. This was done by investigating alterations to the intrinsic functional architecture of speech-language processes of patients with PDS before and after a short-term intervention. Methods: The resting-state functional connectivity and cortical thickness were examined before and after the intervention. The structural data were used to validate the functional results. Fifteen stuttering patients who received intervention, 13 stuttering patients who did not receive intervention, and 13 fluent controls participated. Results: Before the intervention, both groups of PDS patients showed significant RSFC and cortical thickness reductions in the left pars-opercularis and RSFC increases in the cerebellum, as compared to fluent controls. The intervention was effective in reducing stuttering in PDS- patients and lowering their RSFC in the cerebellum to the level of fluent controls. The intervention effect was specific to the PDS-group. The intervention did not change RSFC and cortical thickness in the left PO, which remained at its preintervention level. Conclusions: The results suggest that the left PO is a locus where the intrinsic functional architecture of speech-language processes is altered in PDS patients, suggesting an etiologic role of this region in PDS. The cerebellum showed intervention-induced neural reorganization, suggesting a compensatory response when stuttering occurs. Copyright © 2012 by AAN Enterprises, Inc.

© 2015 Macmillan Publishers Limited All rights reserved. Genome-wide gene expression measurements have enabled comprehensive studies that integrate the changes of gene expression and phenotypic information to uncover their novel associations. Here we reported the association analysis between psychophysical phenotypes and genome-wide gene expression changes in human adaptation to one of the most extreme climates on Earth, the Antarctic Dome Argus. Dome A is the highest ice feature in Antarctica, and may be the coldest, driest and windiest location on earth. It is considered unapproachable due to its hostile environment. In 2007, a Chinese team of 17 male explorers made the expedition to Dome A for scientific investigation. Overall, 133 psychophysical phenotypes were recorded, and genome-wide gene expression profiles from the blood samples of the explorers were measured before their departure and upon their arrival at Dome A. We found that mood disturbances, including tension, depression, anger and fatigue, had a strong, positive, linear relationship with the level of a male sex hormone, testosterone, using the Pearson correlation coefficient analysis. We also demonstrated that significantly lowest-level Gene Ontology groups in changes of gene expression in blood cells with erythrocyte removal were consistent with the adaptation of the psychophysical characteristics. Interestingly, we discovered a list of genes that were strongly related to significant phenotypes using phenotype and gene expression PCC analysis. Importantly, among the 70 genes that were identified, most were significantly related to mood disturbances, where 42 genes have been reported in the literature mining, suggesting that the other 28 genes were likely novel genes involved in the mood disturbance mechanism. Taken together, our association analysis provides a reliable method to uncover novel genes and mechanisms related to phenotypes, although further studies are needed.

© 2015 Taylor & Francis. This analysis compares the climate impacts over North America during winter associated with various El Niño-Southern Oscillation indices, including the Niño 3.4 index, the leading tropical Pacific outgoing longwave radiation and sea surface temperature covariability, and the eastern Pacific and central Pacific types of ENSO identified from both partial-regression-empirical orthogonal function and regression-EOF approaches. The traditional Niño 3.4 SST index is found to be optimal for monitoring the tropical Pacific OLR-SST covariability and for the tropical SST impact on North America. The circulation anomalies associated with the Niño 3.4 index project on both the Pacific/North American and Tropical/Northern Hemisphere patterns. The ENSO associated with the PNA tends to come from both the EP and CP ENSOs, whereas that associated with the TNH comes more from the EP ENSO. The variability of ENSO significantly affects North American temperature and precipitation, as well as temperature and precipitation extremes. For either the EP or CP types of ENSO, qualitatively similar patterns of climate and climate extreme anomalies are apparent associated with the indices identified by the two EOF approaches, with differences mainly in the anomalous amplitude. The anomalous patterns are generally field significant over North America for the EP ENSO but not field significant for the CP ENSO. The circulation anomalies associated with ENSO are reinforced and maintained by synoptic vorticity fluxes in the upper troposphere. The anomalous surface temperature is mainly determined by the anomalies in surface radiative heating in the face of upward surface longwave radiative damping. The precipitation anomalies are supported by the vertically integrated moisture transport. The differences in atmospheric circulation, surface temperature, and precipitation among the various ENSO indices, including the intensity and spatial structure of the fields, can be attributed to the corresponding differences in synoptic eddy vorticity forcing, surface radiative heating, and vertically integrated moisture transport.

Aneuploidy with chromosome instability is a cancer hallmark. We studied chromosome 7 copy number variation in gliomas and in primary cultures derived from them. We found tumor heterogeneity with cells having Chr7-CNV commonly occurs in gliomas, with a higher percentage of cells in high-grade gliomas carrying more than 2 copies of Chr7, as compared to low-grade gliomas. Interestingly, all Chr7-aneuploid cell types in the parental culture of established glioma cell lines reappeared in single-cell-derived subcultures. We then characterized the biology of three syngeneic glioma cultures dominated by different Chr7-aneuploid cell types. We found phenotypic divergence for cells following Chr7 missegregation, which benefited overall tumor growth in vitro and in vivo. Mathematical modeling suggested the involvement of chromosome instability and interactions among cell subpopulations in restoring the optimal equilibrium of tumor cell types. Both our experimental data and mathematical modeling demonstrated that the complexity of tumor heterogeneity could be enhanced by the existence of chromosomes with structural abnormality, in addition to their mis-segregations. Overall, our findings show, for the first time, the involvement of chromosome instability in maintaining tumor heterogeneity, which underlies the enhanced growth, persistence and treatment resistance of cancers. © 2013 Hu et al.

The COVID-19 pandemic has created enormous challenges for organizations and employees. Due to the effectiveness of idiosyncratic deals in management practices, more and more organizations use this human resource management tool to address the challenges posed by the COVID-19 pandemic. However, whether there are potential risks or negative effects of i-deals in the COVID-19 pandemic environment is not very clear. Drawing upon social cognitive theory, we proposed that i-deals may foment focal employees’ unethical behavior by triggering their hubristic pride, and such process may be moderated by their trait of grandiose narcissism. We conducted a survey during the COVID-19 outbreak and tested our hypotheses with 492 samples from Shandong Province, China. Consistent with predictions, we found a positive relationship between i-deals and hubristic pride, which, in turn, increased their unethical behavior. And the relationship between i-deals and unethical behavior was mediated by hubristic pride. Furthermore, grandiose narcissism strengthened the positive relationship between i-deals and hubristic pride, as well as the indirect effect of i-deals on unethical behavior via hubristic pride. Our findings contributed to the literature on i-deals and provided guidance for organizations to address the challenges posed by the COVID-19 pandemic.