Tissue-specific gene expression requires coordinated control of gene-proximal and -distal cis-regulatory elements (CREs), yet functional analysis of gene-distal CREs such as enhancers remains ...challenging. Here we describe CRISPR/dCas9-based enhancer-targeting epigenetic editing systems, enCRISPRa and enCRISPRi, for efficient analysis of enhancer function in situ and in vivo. Using dual effectors capable of re-writing enhancer-associated chromatin modifications, we show that enCRISPRa and enCRISPRi modulate gene transcription by remodeling local epigenetic landscapes at sgRNA-targeted enhancers and associated genes. Comparing with existing methods, the improved systems display more robust perturbations of enhancer activity and gene transcription with minimal off-targets. Allele-specific targeting of enCRISPRa to oncogenic TAL1 super-enhancer modulates TAL1 expression and cancer progression in xenotransplants. Single or multi-loci perturbations of lineage-specific enhancers using an enCRISPRi knock-in mouse establish in vivo evidence for lineage-restricted essentiality of developmental enhancers during hematopoiesis. Hence, enhancer-targeting CRISPR epigenetic editing provides opportunities for interrogating enhancer function in native biological contexts.
In this paper, a unified form for robust Gaussian information filtering based on M-estimate is proposed, which can incorporate robust weight functions with zero weight for large residues. The ...proposed information filtering framework can avoid the numerical problem introduced by the zero weight in the Kalman filtering framework. Simulation results show the efficiency and superiority of the proposed robust filters over the nonrobust filter against heavy-tailed measurement noises.
This paper proposes a modified unscented Kalman filter (UKF) with both adaptivity and robustness. In the proposed filter, the adaptivity is achieved by estimating the time-varying measurement noise ...covariance based on variational Bayesian (VB) approximation. The robustness is achieved by modifying the filter update based on Huber's M-estimation and Gaussian-Newton iterated method. In Gaussian assumptions, the proposed filter has a comparable filtering accuracy with the original UKF and better filtering consistency. When the measurement noise covariance is time-varying and there are outliers in the measurements, the proposed filter can outperform UKF and other adaptive or robust filters (such as VB-based UKF and Huber-based UKF) in terms of both filter accuracy and consistency. The efficacy of the proposed filter is demonstrated through the numerical simulation test and integrated navigation shipborne test.
In this paper, the optimization-based alignment (OBA) methods are investigated with the main focus on the vector observation construction procedures for the strapdown inertial navigation system ...(SINS). The contributions of this study are twofold. First, the OBA method is extended to be able to estimate the gyroscope biases coupled with the attitude based on the construction process of the existing OBA methods. This extension transforms the initial alignment into an attitude estimation problem that can be solved by using the nonlinear filtering algorithms. The second contribution is the comprehensive evaluation of the OBA methods and their extensions with different vector observations construction procedures in terms of convergence speed and steady-state estimate by using field test data collected from different grades of SINS. This study is expected to facilitate the selection of appropriate OBA methods for different grades of SINS.
With the continuous development and improvement in Internet-of-Things (IoT) technology, indoor localization has received considerable attention. Particularly, owing to its unique advantages, the ...Wi-Fi fingerprint-based indoor-localization method has been widely investigated. However, achieving high-accuracy localization remains a challenge. This study proposes an application of the standard particle swarm optimization algorithm to Wi-Fi fingerprint-based indoor localization, wherein a new two-panel fingerprint homogeneity model is adopted to characterize fingerprint similarity to achieve better performance. In addition, the performance of the localization method is experimentally verified. The proposed localization method outperforms conventional algorithms, with improvements in the localization accuracy of 15.32%, 15.91%, 32.38%, and 36.64%, compared to those of KNN, SVM, LR, and RF, respectively.
The integration of the inertial navigation system and the global positioning system (INS/GPS) is a widely used procedure for position and attitude determination applications. The Kalman type filter ...(KTF) is the primary mechanism to perform the integration. In the KTF, the process noise is always assumed to be Gaussian distribution, which may be violated by the vehicle's severe maneuver, resulting in a much degraded performance. In this paper, the Huber's M-estimation methodology is investigated to suppress the process uncertainty, founded on the cascaded form of the M-estimation-based Kalman filter. An iterated algorithm is designed to construct the weighted matrix to rescale the prior state estimate covariance. The proposed process uncertainty robust algorithm is embedded into the newly derived modified unscented quaternion estimator to perform the standard inertial navigation equations-based INS/GPS integration. The car-mounted experiments are carried out to validate the proposed method against the process uncertainty.
Cis-regulatory elements (CREs) are commonly recognized by correlative chromatin features, yet the molecular composition of the vast majority of CREs in chromatin remains unknown. Here, we describe ...a CRISPR affinity purification in situ of regulatory elements (CAPTURE) approach to unbiasedly identify locus-specific chromatin-regulating protein complexes and long-range DNA interactions. Using an in vivo biotinylated nuclease-deficient Cas9 protein and sequence-specific guide RNAs, we show high-resolution and selective isolation of chromatin interactions at a single-copy genomic locus. Purification of human telomeres using CAPTURE identifies known and new telomeric factors. In situ capture of individual constituents of the enhancer cluster controlling human β-globin genes establishes evidence for composition-based hierarchical organization. Furthermore, unbiased analysis of chromatin interactions at disease-associated cis-elements and developmentally regulated super-enhancers reveals spatial features that causally control gene transcription. Thus, comprehensive and unbiased analysis of locus-specific regulatory composition provides mechanistic insight into genome structure and function in development and disease.
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•dCas9 capture enables analysis of locus-specific chromatin-regulating proteome•dCas9 capture identifies high-resolution locus-specific long-range DNA interactions•Capture of disease-associated CREs uncovers mechanisms for β-globin disorders•Capture of super-enhancers reveals composition-based hierarchical structure
A biotinylated dCas9-based method for simultaneously studying long-range DNA interactions and chromatin-associated proteins at any genomic location.
The dissipation and residue levels of thiacloprid, spirotetramat and its four metabolites residues in cowpeas were investigated under field conditions. The QuEChERS technique with high-performance ...liquid chromatography tandem mass spectrometry (HPLC-MS/MS) was used to detect thiacloprid, spirotetramat and its four metabolites residues content in cowpeas. The recoveries were 81.3-95.1% at a spike level of 0.005-0.5 mg/kg, the relative standard deviations (RSDs) were 2.1-9.5%. The dissipation kinetics data showed that thiacloprid and spirotetramat in cowpeas were degraded with the half-lives of 1.14-1.54 days and 1.25-2.79 days. The terminal residues of thiacloprid and spirotetramat were 0.0255-0.4570 mg kg
and 0.0314-0.3070 mg kg
after application 2 times with a pre-harvest interval (PHI) of 3 days under the designed dosages. The chronic and acute dietary exposure assessment risk quotient (RQ) values of thiacloprid in cowpeas for different consumers were 2.44-4.41% and 8.72-15.78%, respectively, and those of spirotetramat were 1.03-1.87% and 0.18-0.32%, respectively, all of the RQ values were lower than 100%. The dietary risk of thiacloprid through cowpeas to consumers was higher than spirotetramat. The results from this study are important reference for Chinese governments to develop criteria for the safe and rational use of thiacloprid and spirotetramat, setting maximum residue levels (MRLs), monitoring the quality safety of agricultural products and protecting consumer health.
Recent studies have highlighted super-enhancers (SEs) as important regulatory elements for gene expression, but their intrinsic properties remain incompletely characterized. Through an integrative ...analysis of Hi-C and ChIP-seq data, here we find that a significant fraction of SEs are hierarchically organized, containing both hub and non-hub enhancers. Hub enhancers share similar histone marks with non-hub enhancers, but are distinctly associated with cohesin and CTCF binding sites and disease-associated genetic variants. Genetic ablation of hub enhancers results in profound defects in gene activation and local chromatin landscape. As such, hub enhancers are the major constituents responsible for SE functional and structural organization.
In response to the lack of specific demonstration and analysis of the research on the necessity of the Lie group strapdown inertial integrated navigation error model based on the Euler angle, two ...common integrated navigation systems, strapdown inertial navigation system/global navigation satellite system (SINS/GNSS) and strapdown inertial navigation system/doppler velocity log (SINS/DVL), are used as subjects, and the piecewise constant system (PWCS) matrix, based on the Lie group error model, is established. From three aspects of variance estimation, the observability and performance of the system with large misalignment angles for low, medium, and high accuracy levels, traditional error model, Lie group left error model, and right error model are compared. The necessity of research on Lie group error model is analyzed quantitatively and qualitatively. The experimental results show that Lie group error model has better stability of variance estimation, estimation accuracy, and observability than traditional error model, as well as higher practical value.
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