Ying Duan

© 2014 Elsevier Inc. All rights reserved.Sequence-programmable transcription activator-like effector proteins have emerged as a highly efficient tool for genome engineering. Recent crystal structures depict a transition between an open unbound solenoid and more compact DNA-bound solenoid formed by the 34 amino acid repeats. How TALEs switch conformation between these two forms without substantial energetic compensation, and how the repeat-variable di-residues discriminate between the cognate base and other bases still remain unclear. Computational analysis on these two aspects of TALE-DNA interaction mechanism has been conducted in order to achieve a better understanding of the energetics. High elasticity was observed in the molecular dynamics simulations of DNA-free TALE structure that started from the bound conformation where it sampled a wide range of conformations including the experimentally determined apo and bound conformations. This elastic feature was also observed in the simulations starting from the apo form which suggests low free energy barrier between the two conformations and small compensation required upon binding. To analyze binding specificity, we performed free energy calculations of various combinations of RVDs and bases using Poisson-Boltzmann surface area and other approaches. The PBSA calculations indicated that the native RVD-base structures had lower binding free energy than mismatched structures for most of the RVDs examined. Our theoretical analyses provided new insight on the dynamics and energetics of TALE-DNA binding mechanism.

© 2014 Nature America, Inc. All rights reserved. Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated 1/42,000, 1/43,700 and 1/49,500 SNPs explained 1/421%, 1/424% and 1/429% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/I 2-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number of causal variants.

ObjectiveCancer and its treatments affect patients’ fertility potential. This study examined the prevalence of reproductive concerns and their relationship with metacognitions among Chinese young adult female cancer survivors.MethodsA total of 318 YAFCS completed an online survey from March to December 2021. Participants reported sociodemographic characteristics, reproductive concerns and metacognitions. Reproductive concerns were measured using the Reproductive Concerns after Cancer scale, and metacognitions were measured by the Short Form of Metacognitions Questionnaire. We used Pearson correlation analysis to examine associations between metacognitions and reproductive concerns across multiple domains and multivariable linear regression to determine the influencing factors of reproductive concerns.ResultsThe mean score of reproductive concern among YAFCS was 49.97 ± 12.52. A total of 57.9% of participants reported a high level of concern regarding at least one dimension of reproductive concerns, and they were most concerned about their child’s health and least concerned about partner disclosure of fertility status. We also found a moderate association between RCAC and MCQ-30 scores. In multivariate analyses, metacognitions, especially negative metacognitive beliefs had an impact on reproductive concerns among YAFCS.ConclusionHigher reproductive concerns were associated with higher metacognitions among YAFCS, especially with negative metacognitive beliefs. Oncology professionals should pay attention to assessing reproductive concerns in patients who want to have children or who have no children. Moreover, metacognitive beliefs may be an intervention target for alleviating reproductive concerns among YAFCS.

Drug addiction is viewed as a maladaptive memory induced by contextual cues even in the abstinent state. However, the variations of hedonia and appetite induced by the context during the abstinence have been neglected. To distinguish the representative behaviors between hedonia and appetite, micro-behaviors in abstinent animal such as psycho-activity and drug seeking behaviors were observed in morphine conditioned place preference (CPP). To confirm the different effects of reward between drug and natural reward, a palatable food CPP paradigm was compared in current work. After a 10-day training in CPP with morphine or food, the preference was tested on day 1, 14, 28, and the changes of micro-behaviors were analyzed further. Our data showed that tree shrews treated with morphine performed more jumps on day 1 and more visits to saline paired side on day 28, which indicated a featured behavioral transition from psycho-activity to seeking behavior during drug abstinence. Meanwhile, food-conditioned animals only displayed obvious seeking behaviors in the three tests. The results suggest that the variations of micro-behaviors could imply such a transition from hedonic response to appetitive behaviors during morphine abstinence, which provided a potential behavioral basis for further neural mechanism studies.