Programmable base editing of zebrafish genome using a modified CRISPR-Cas9 system.

Precise genetic modifications in model animals are essential for biomedical research. Here, we report a programmable "base editing" system to induce precise base conversion with high efficiency in zebrafish. Using cytidine deaminase fused to Cas9 nickase, up to 28% of site-specific single-base mutations are achieved in multiple gene loci. In addition, an engineered Cas9-VQR variant with 5'-NGA PAM specificities is used to induce base conversion in zebrafish. This shows that Cas9 variants can be used to expand the utility of this technology. Collectively, the targeted base editing system represents a strategy for precise and effective genome editing in zebrafish.The use of base editing enables precise genetic modifications in model animals. Here the authors show high efficient single-base editing in zebrafish using modified Cas9 and its VQR variant with an altered PAM specificity

A SUPERVISED SINGULAR VALUE DECOMPOSITION FOR INDEPENDENT COMPONENT ANALYSIS OF fMRI

Functional Magnetic Resonance Imaging (fMRI) is a non-invasive tech-nique for studying the brain activity. The data acquisition process results a tempo-ral sequence of 3D brain images. Due to the high sensitivity of MR scanners, spikes are commonly observed in the data. Along with the temporal and spatial features of fMRI data, this artifact raises a challenging problem in the statistical analysis. In this paper, we introduce a supervised singular value decomposition technique as a data reduction step of independent component analysis (ICA), which is an effective tool for exploring spatio-temporal features in fMRI data. Two major advantages are discussed: first, the proposed method improves the robustness of ICA against spikes; second, the method uses the fMRI experimental designs to guide the fully data-driven ICA, yielding a more computationally efficient procedure and highly interpretable results. The advantages are demonstrated using spatio-temporal sim-ulation studies as well as a data analysis

Light dark matter and Z′Z' dark force at colliders

Light Dark Matter, $<10$ GeV, with sizable direct detection rate is an interesting and less explored scenario. Collider searches can be very powerful, such as through the channel in which a pair of dark matter particle are produced in association with a jet. It is a generic possibility that the mediator of the interaction between DM and the nucleus will also be accessible at the Tevatron and the LHC. Therefore, collider search of the mediator can provide a more comprehensive probe of the dark matter and its interactions. In this article, to demonstrate the complementarity of these two approaches, we focus on the possibility of the mediator being a new $U(1)'$ gauge boson, which is probably the simplest model which allows a large direct detection cross section for a light dark matter candidate. We combine searches in the monojet+MET channel and dijet resonance search for the mediator. We find that for the mass of $Z'$ between 250 GeV and 4 TeV, resonance searches at the colliders provide stronger constraints on this model than the monojet+MET searches.Comment: 23 pages and 14 figure

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Effect of pre-corrosion on damage evolution and crack propagation in aluminum alloy 7050-T7651

This paper investigates the effects of pre-corrosion on the tensile behavior of aluminum alloy 7050-T7651. A combined experimental approach involving digital image correlation, scanning electron microscopy, and tensile testing is presented for quantitative and qualitative analysis. A tensile damage model is presented for plasticity-induced, post-corrosion mechanical damage for interpretation and identification of damage and cracking thresholds. Although multiple corrosion-induced cracks evolve simultaneously in diffuse regions, propagation and coalescence of the main cracks, originating from key damage regions, dominate the failure process. A combined corrosion and mechanical damage model was used to successfully predict the effects of pre-corrosion on the tensile stress-strain response.Highlightscenter dot Full-field macro-microscale characterization of tensile damage and cracking for aluminum alloy using digital image correlation, scanning electron microscopy, and tensile testing.center dot Corrosion-plasticity damage mechanics model for effects of pre-corrosion.center dot Identification of post-corrosion evolution of damage, strain, micro-cracking initiation, and coalescence, as well as crack orientation and propagation.center dot Multiple diffuse cracks evolve simultaneously, but propagation-coalescence of main cracks in key damage regions dominates failure process.This research was supported by the National Natural Science Foundation of China (NSFC, Grant Nos. 11502285 and 11472298), the Science Foundation Ireland (SFI, Grant No. 14/IA/2604), and the Fundamental Research Funds for the Central Universities (FRFCU, Grant No. 3122014H006).peer-reviewe

Robust and Efficient Frequency Estimator for Undersampled Waveforms Based on Frequency Offset Recognition.

This paper proposes an efficient frequency estimator based on Chinese Remainder Theorem for undersampled waveforms. Due to the emphasis on frequency offset recognition (i.e., frequency shift and compensation) of small-point DFT remainders, compared to estimators using large-point DFT remainders, it can achieve higher noise robustness in low signal-to-noise ratio (SNR) cases and higher accuracy in high SNR cases. Numerical results show that, by incorporating a remainder screening method and the Tsui spectrum corrector, the proposed estimator not only lowers the SNR threshold of detection, but also provides a higher accuracy than the large-point DFT estimator when the DFT size decreases to 1/90 of the latter case

Effect of pre-corrosion on damage evolution and crack propagation in aluminum alloy 7050-T7651

This paper investigates the effects of pre-corrosion on the tensile behavior of aluminum alloy 7050-T7651. A combined experimental approach involving digital image correlation, scanning electron microscopy, and tensile testing is presented for quantitative and qualitative analysis. A tensile damage model is presented for plasticity-induced, post-corrosion mechanical damage for interpretation and identification of damage and cracking thresholds. Although multiple corrosion-induced cracks evolve simultaneously in diffuse regions, propagation and coalescence of the main cracks, originating from key damage regions, dominate the failure process. A combined corrosion and mechanical damage model was used to successfully predict the effects of pre-corrosion on the tensile stress-strain response.Highlightscenter dot Full-field macro-microscale characterization of tensile damage and cracking for aluminum alloy using digital image correlation, scanning electron microscopy, and tensile testing.center dot Corrosion-plasticity damage mechanics model for effects of pre-corrosion.center dot Identification of post-corrosion evolution of damage, strain, micro-cracking initiation, and coalescence, as well as crack orientation and propagation.center dot Multiple diffuse cracks evolve simultaneously, but propagation-coalescence of main cracks in key damage regions dominates failure process.This research was supported by the National Natural Science Foundation of China (NSFC, Grant Nos. 11502285 and 11472298), the Science Foundation Ireland (SFI, Grant No. 14/IA/2604), and the Fundamental Research Funds for the Central Universities (FRFCU, Grant No. 3122014H006).peer-reviewe

Precise A•T to G•C base editing in the zebrafish genome

Abstract Background Base editors are a class of genome editing tools with the ability to efficiently induce point mutations in genomic DNA, without inducing double-strand breaks or relying on homology-direct repair as in other such technologies. Recently, adenine base editors (ABEs) have been developed to mediate the conversion of A•T to G•C in genomic DNA of human cells, mice, and plants. Here, we investigated the activity and efficiency of several adenine base editors in zebrafish and showed that base editing can be used to create new models of pathogenic diseases caused by point mutations. Results The original ABE7.10 exhibits almost no activity in zebrafish. After codon optimization, we found that a zABE7.10 variant could induce targeted conversion of adenine to guanine in zebrafish at multiple tested genomic loci, and all the target sites showed a high rate of germline targeting efficiency. Furthermore, using this system, we established a zebrafish model of 5q-Syndrome that contained a new point mutation in rps14. The further modification of zABE7.10 by a bipartite nuclear localization signals (bpNLS) resulted in 1.96-fold average improvement in ABE-mediated editing efficiency at four sites. Conclusions Collectively, this system, designated as zABE7.10, provides a strategy to perform A•T to G•C base editing in zebrafish and enhances its capacity to model human diseases