Modulating the activity of CRISPR/Cas9 genome editing by small molecules

The use of the bacterial-derived CRISPR/Cas9 genome editing system offers enormous opportunities to treat human genetic diseases. However, the potency of CRISPR/Cas9 is limited by the low precise genome editing efficiency and continuous activity of Cas9. The development of cell permeable small molecules is promising approach for precise control of Cas9 activity and may greatly enhance the application of genome editing in academic, industrial, and clinical settings. In this thesis, we found that the efficiency of CRISPR/Cas9-mediated genome editing can be modulated by histone deacetylases (HDACs) inhibitors. In order to identify potential Cas9 inhibitors and enhancers we developed a living cell-based high-throughput screening platform. Using this assay, we identified two novel potent small molecule Cas9 inhibitors that switch off Cas9 activity as well as a new potent Cas9 enhancer. These molecules inhibited/enhanced the CRISPR/Cas9-mediated genome editing in biochemical, eukaryotic, and prokaryotic cell studies. Interestingly, the potent Cas9 enhancer was obtained by a minor variation from one of the Cas9 inhibitors. Next, we showed that the Cas9 inhibitors and enhancer can modify the Cas9 activity by binding at the RuvC active site of the Cas9 endonuclease. Our results provide a practical and possibly clinically applicable way to precisely modulate CRISPR/Cas9-mediated genome editing activity using small molecules. These findings also gain new insight into the interactions between small molecules and the Cas9 protein and may extend the application of genome editing techniques

Exploiting Image Local And Nonlocal Consistency For Mixed Gaussian-Impulse Noise Removal

Most existing image denoising algorithms can only deal with a single type of noise, which violates the fact that the noisy observed images in practice are often suffered from more than one type of noise during the process of acquisition and transmission. In this paper, we propose a new variational algorithm for mixed Gaussian-impulse noise removal by exploiting image local consistency and nonlocal consistency simultaneously. Specifically, the local consistency is measured by a hyper-Laplace prior, enforcing the local smoothness of images, while the nonlocal consistency is measured by three-dimensional sparsity of similar blocks, enforcing the nonlocal self-similarity of natural images. Moreover, a Split-Bregman based technique is developed to solve the above optimization problem efficiently. Extensive experiments for mixed Gaussian plus impulse noise show that significant performance improvements over the current state-of-the-art schemes have been achieved, which substantiates the effectiveness of the proposed algorithm.Comment: 6 pages, 4 figures, 3 tables, to be published at IEEE Int. Conf. on Multimedia & Expo (ICME) 201

Image Super-Resolution via Dual-Dictionary Learning And Sparse Representation

Learning-based image super-resolution aims to reconstruct high-frequency (HF) details from the prior model trained by a set of high- and low-resolution image patches. In this paper, HF to be estimated is considered as a combination of two components: main high-frequency (MHF) and residual high-frequency (RHF), and we propose a novel image super-resolution method via dual-dictionary learning and sparse representation, which consists of the main dictionary learning and the residual dictionary learning, to recover MHF and RHF respectively. Extensive experimental results on test images validate that by employing the proposed two-layer progressive scheme, more image details can be recovered and much better results can be achieved than the state-of-the-art algorithms in terms of both PSNR and visual perception.Comment: 4 pages, 4 figures, 1 table, to be published at IEEE Int. Symposium of Circuits and Systems (ISCAS) 201

Dyslipidemia and the Prevalence of Hypertension: A Cross-Sectional Study Based on Chinese Adults Without Type 2 Diabetes Mellitus

Background: In clinical practice, it is frequently observed that patients with hypertension often coexist with dyslipidemia. However, studies on atherosclerotic indices and the prevalence of hypertension are still limited. The purpose of this study was to assess the relationship between atherosclerotic indices and the prevalence of hypertension in Chinese adults without type 2 diabetes mellitus. Methods: In this paper, a cross-sectional study was conducted based on 117,056 adults in 11 Chinese cities (Shanghai, Beijing, Wuhan, Suzhou, Shenzhen, Changzhou, Nantong, Guangzhou, Hefei, Nanjing, and Chengdu) from 2010 to 2016. Besides, the raw data was obtained from the public database (www.Datadryad.org), while eight atherosclerosis indices namely the atherogenic coefficient (AC), Castelli's risk index I (CRI-I) and II (CRI-II), the atherogenic index of plasma (AIP), the cholesterol index, the lipoprotein combined index (LCI), non-high-density lipoprotein cholesterol (non-HDL-C) and triglycerides/high-density lipoprotein cholesterol (TG/HDL-C) were analyzed in this study. Apart from that, two groups of continuous variables were measured using the Mann-Whitney test, and categorical variables were analyzed using the Chi-square test. Differences between multiple groups of continuous variables were investigated using Kruskal-Wallis one-way analysis of variance (ANOVA) and Dunn's test. Furthermore, Spearman correlation analysis and multivariate logistic regression analyses were performed to assess the relationship between atherosclerotic indices and blood pressure levels, and the prevalence of hypertension, respectively. The results of multivariate logistic regression analyses were expressed as the odds ratio (OR) and their corresponding 95% confidence intervals (CIs). Moreover, the receiver operating characteristic (ROC) curve was depicted to further analyze the predictive value of the atherosclerotic indices on the prevalence of hypertension. Results: The atherosclerosis indices were higher in the hypertensive population compared to those in the normotensive population. Meanwhile, systolic blood pressure (SBP) and diastolic blood pressure (DBP) were linearly and positively correlated with atherosclerotic indices. In addition, multivariate logistic regression analysis showed that the cholesterol index and non-HDL-C were observed to be positively associated with the prevalence of hypertension (p for trend < 0.05). Moreover, the prevalence of hypertension increased by 3.7% (OR: 1.037; 95% CI: 1.009-1.065; p = 0.009) and 6.1% (OR: 1.06; 95% CI: 1.033-1.091; p < 0.001), respectively, as per 1-standard deviation (SD) increase in the cholesterol index and non-HDL-C. Beyond that, ROC analysis demonstrated that the cholesterol index and non-HDL-C have a good predictive value for the prevalence of hypertension in women, with under the ROC curve (AUC) of 0.659 and 0.684 and cut-off values of 47.94 and 134.34 mg/dl, accordingly. Conclusions: In Chinese adults without type 2 diabetes mellitus, atherosclerotic indices were significantly higher in hypertensive populations compared with those in normotensive populations, regardless of hypertension levels. Meanwhile, SBP and DBP were linearly and positively related to atherosclerotic indices. Besides, the cholesterol index and non-HDL-C were independent risk factors for the prevalence of hypertension, and they could be adopted for effectively predicting the prevalence of hypertension in women

Modulating CRISPR/Cas9 genome-editing activity by small molecules

Clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9)-mediated genome engineering has become a standard procedure for creating genetic and epigenetic changes of DNA molecules in basic biology, biotechnology, and medicine. However, its versatile applications have been hampered by its overall low precise gene modification efficiency and uncontrollable prolonged Cas9 activity. Therefore, overcoming these problems could broaden the therapeutic use of CRISPR/Cas9-based technologies. Here, we review small molecules with the clinical potential to precisely modulate CRISPR/Cas9-mediated genome-editing activity and discuss their mechanisms of action. Based on these data, we suggest that direct-acting small molecules for Cas9 are more suitable for precisely regulating Cas9 activity. These findings provide useful information for the identification of novel small-molecule enhancers and inhibitors of Cas9 and Cas9-associated endonucleases

The Effect of Isostatic Pressing on the Dielectric Properties of Screen Printed Ba\u3csub\u3e0.5\u3c/sub\u3eSr\u3csub\u3e0.5\u3c/sub\u3eTiO\u3csub\u3e3\u3c/sub\u3e Thick Films

Ba0.5Sr0.5TiO3 thick films with B2O3–Li2O glass sintering aid were prepared by the screen printing method on Al2O3 substrates. A 200 MPa isostatic pressure was applied to the films before sintering. After being sintered at 950∘C, lower porosity and denser microstructure was obtained compared with the films without isostatic pressing. The dielectric constant and dielectric loss were 238 and 0.0028, respectively. A tunability of 61.7% was obtained for the isostatic pressed films, a 27.8% enhancement compared to unpressurized films. These results suggest that isostatic pressing is an effective way to prepare dielectric thick films with dense microstructure, low dielectric loss, and high tunability