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Improving Plant Genome Editing with High-Fidelity xCas9 and non-canonical PAM-Targeting Cas9-NG

Molecular Plant 2019年第7期12卷 1027-1036页

作者： Zhaohui Zhong Simon Sretenovic Qiurong Ren Lijia Yang Yu Bao Caiyan Qi Mingzhu Yuan Yao He Shishi Liu Xiaopei Liu Jiaheng Wang Lan Huang Yan Wang Dibin Baby David Wang Tao Zhang Yiping Qi Yong Zhang Department of Biotechnology School of Life Sciences and Technology Center for Informational Biology University of 曰ectronic Science and Technology of China Room 216 Main Building No. 4 Section 2 North Jianshe Road Chengdu 610054 China Department of Plant Science and Landscape Architecture University of Maryland College Park MD 20742 USA Jiangsu Key Laboratory of Crop Genetics and Physiology Co-Innovation Center for Modern Production Technology of Grain Crops Key Laboratory of Plant Functional Genomics of the Ministry of Education Yangzhou University Yangzhou 225009 China Joint International Research Laboratory of Agriculture and Agri-Product Safety of Ministry of Education of China Yangzhou University Yangzhou 225009 China Indian Institute of Science Education and Research Timpati Andhra Pradesh 517507 India Seven Lakes High School Katy TX 77494 USA Institute for Bioscience and Biotechnology Research University of Maryland Rockville MD 20850 USA

Two recently engineered SpCas9 variants, namely xCas9 and Cas9-NG, show promising potential in improving targeting specificity and broadening the targeting range. In this study, we evaluated these Cas9 variants in the model and crop plant, rice. We first tested xCas9-3.7, the most effective xCas9 variant in mammalian cells, for targeted mutagenesis at 16 possible NGN PAM (protospacer adjacent motif) combinations in duplicates. xCas9 exhibited nearly equivalent editing efficiency to wild-type Cas9 (Cas9-WT) at most canonical NGG PAM sites tested, whereas it showed limited activity at non-canonical NGH (H = A, C, T) PAM sites. High editing efficiency of xCas9 at NGG PAMs was further demonstrated with C to T base editing by both rAPOBECI and PmCDAI cytidine deaminases. With mismatched sgRNAs, we found that xCas9 had improved targeting specificity over the Cas9-WT. Furthermore, we tested two Cas9-NG variants, Cas9-NGv1 and Cas9-NG, for targeting NGN PAMs. Both Cas9-NG variants showed higher editing efficiency at most non-canonical NG PAM sites tested, and enabled much more efficient editing than xCas9 at AT-rich PAM sites such as GAT, GAA, and CAA. Nevertheless, we found that Cas9-NG variants showed significant reduced activity at the canonical NGG PAM sites. In stable transgenic rice lines, we demonstrated that Cas9-NG had much higher editing efficiency than Cas9-NGv1 and xCas9 at NG PAM sites. To expand the base-editing scope, we developed an efficient C to T base-editing system by making fusion of Cas9-NG nickase (D10A version), PmCDAI, and UGI. Taken together, our work benchmarked xCas9 as a high-fidelity nuclease for targeting canonical NGG PAMs and Cas9-NG as a preferred variant for targeting relaxed PAMs for plant genome editing.

关键词： xCas9 Cas9-NG high fidelity non-canonical PAM base editing

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non-canonical scalar implicatures, face/politeness considerations, and neo-Gricean pragmatics

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外语教学与研究 2020年第1期52卷 25-39页

作者：黄衍 School of Cultures Languages and LinguisticsUniversity of AucklandPrivate Bag 92019AucklandNew Zealand

One of the politeness strategies,which has recently been observed,is the use of a semantically weak scalar expression to implicate the meaning of one or more of its stronger alternatives in a face-threatening context-a speech situation in which a loss of face can potentially be induced for the addressee,the speaker or both-out of politeness concerns.I call this type of marked scalar implicatures‘non-canonical scalar implicatures’.This article provides an informed discussion of the linguistic phenomenon in a few languages and presents a new analysis of it within the neo-Gricean pragmatic framework.

关键词： scalar implicatures standard scalar implicatures non-canonical scalar implicatures face politeness neo-Gricean pragmatics conversation analysis(CA)

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The noncanonical inflammasome in health and disease

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Infectious Medicine 2022年第3期1卷 208-216页

作者： Jason Cahoon Duomeng Yang Penghua Wang Department of Immunology School of MedicineUConn HealthFarmingtonCT 06030USA

Innate immune signaling plays a significant role in the rapid cellular responses against foreign entities.An inflam-masome is a large cytosolic polymer of a pattern recognition receptor with/without an adaptor protein,formed in response to these entities.canonically,an inflammasome can recruit and lead to auto-activation of caspase-1,subsequent maturation and secretion of inflammatory cytokines,and pyroptosis.One particular inflammasome,the noncanonical inflammasome,is formed by caspase-4 or-5(mouse caspase-11)upon binding of lipopolysac-charide and is essential for controlling gram-negative bacterial infection.However,prolonged hyper-activation of the non-canonical inflammasome has been implicated in the pathogenesis of inflammatory diseases and endotox-emia sepsis.This review will summarize the recent advances on the noncanonical inflammasome,its mechanism of activation,key cellular regulators and role in health and disease.

关键词： Inflammasome non-canonical Pyroptosis Inflammatory Caspase

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Updates on the hepatocyte growth factor/c-Met axis in hepatocellular carcinoma and its therapeutic implications

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World Journal of Gastroenterology 2018年第33期24卷 3695-3708页

作者： Javier A García-Vilas Miguelángel Medina Department of Pediatrics University of AlbertaEdmonton T6G 2S2Canada Departamento de Biología Molecular y Bioquímica Facultad de CienciasAndalucía TechUniversidad de MálagaMálaga 29071Spain Unidad 741 de CIBER“de Enfermedades Raras”(CIBERER) Málaga 29071Spain Institute of Biomedical Research in Málaga Málaga 29071Spain

Hepatocellular carcinoma(HCC) is the fifth most common cancer and is the second leading cause of cancer death. Since the diagnosis of HCC is difficult, in many cases patients with HCC are diagnosed advanced stage of development. Hepatocyte growth factor(HGF)/c-mesenchymal-epithelial transition receptor(c-Met) axis is a key signaling pathway in HCC, either via canonical or non-canonical pathways. Available treatments against HCC based upon HGF/c-Met inhibition can increase patient lifespan, but do not reach the expected therapeutic benefits. In HCC, c-Met monomers can bind other receptor monomers, activating several noncanonical signaling pathways, leading to increased cell proliferation, invasion, motility, and drug resistance. All of these processes are enhanced by the tumor microenvironment, with stromal cells contributing to boost tumor progression through oxidative stress, angiogenesis, lymphangiogenesis, inflammation, and fibrosis. Novel treatments against HCC are being explored to modulate other targets such as microR NAs, methyltransferases, and acetyltransferases, which are all involved in the regulation of gene expression in cancer. This review compiles basic knowledge regarding signaling pathways in HCC, and compounds already used or showing potential to be used in clinical trials.

关键词： Hepatocellular carcinoma Hepatocyte growth factor/c-MET Tumor microenvironment c-Met canonical and non-canonical pathways

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Aberrant regulation of Wnt signaling in hepatocellular carcinoma

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World Journal of Gastroenterology 2016年第33期22卷 7486-7499页

作者： Li-Juan Liu Shui-Xiang Xie Ya-Tang Chen Jing-Ling Xue Chuan-Jie Zhang Fan Zhu Department of Medical Microbiology School of MedicineWuhan UniversityWuhan 430071 Hubei Province China Department of Pathogenic Biology Gannan Medical University Gannan 341000 Jiangxi Province China Department of Pathology School of MedicineWuhan UniversityWuhan 430071 Hubei Province China Department of Children Health Care Wuhan Medical Care Center for Women and Children Wuhan 430016 Hubei Province China Hubei Province Key Laboratory of Allergy and Immunology Wuhan 430071 Hubei Province China

Hepatocellular carcinoma(HCC) is one of the most lethal malignancies in the world. Several signaling pathways,including the wingless/int-1(Wnt) signaling pathway,have been shown to be commonly activated in HCC. The Wnt signaling pathway can be triggered via both catenin β1(CTNNB1)-dependent(also known as "canonical") and CTNNB1-independent(often referred to as "non-canonical") pathways. Specifically,the canonical Wnt pathway is one of those most frequently reported in HCC. Aberrant regulation from three complexes(the cell-surface receptor complex,the cytoplasmic destruction complex and the nuclear CTNNB1/T-cell-specific transcription factor/lymphoid enhancer binding factor transcriptional complex) are all involved in HCC. Although the non-canonical Wnt pathway is rarely reported,two main non-canonical pathways,Wnt/planar cell polarity pathway and Wnt/Ca2+ pathway,participate in the regulation of hepatocarcinogenesis. Interestingly,the canonical Wnt pathway is antagonized by non-canonical Wnt signaling in HCC. Moreover,other signaling cascades have also been demonstrated to regulate the Wnt pathway through crosstalk in HCC pathogenesis. This review provides a perspective on the emerging evidence that the aberrant regulation of Wnt signaling is a critical mechanism for the development of HCC. Furthermore,crosstalk between different signaling pathways might be conducive to the development of novel molecular targets of HCC.

关键词： Hepatocellular carcinoma Wingless/int-1 Catenin β1 Crosstalk canonical Wingless/int-1 signaling non-canonical Wingless/int-1 signaling

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Stabilization of coupled orbit-atitude dynamics about an asteroid utilizing Hamiltonian structure

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Astrodynamics 2018年第1期2卷 53-67页

作者： Yue Wang Shijie Xu School of Astronautics Beihang UniversityBeijing 100191China

The gravitationally coupled orbit-attitude dynamics,also called the full dynamics,in which the spacecraft is modeled as a rigid body,is a high-precision model for the motion in the close proximity of an asteroid.A feedback control law is proposed to stabilize relative equilibria of the coupled orbit-attitude motion in a uniformly rotating second degree and order gravity eld by utilizing the Hamiltonian structure.The feedback control law is consisted of potential shaping and energy dissipation.The potential shaping makes the relative equilibrium a minimum of the modi ed Hamiltonian by modifying the potential arti cially.With the energy-Casimir method,it is theoretically proved that an unstable relative equilibrium can always be stabilized in the Lyapunov sense by the potential shaping with sufficiently large feedback gains.Then,the energy dissipation leads the motion to converge to the relative equilibrium.The proposed stabilization control law has a simple form and is easy to implement autonomously,which can be attributed to the utilization of natural dynamical behaviors in the controller design.

关键词： asteroid missions gravitationally coupled orbit-attitude dynamics full dynamics stabilization non-canonical Hamiltonian structure potential shaping

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V-ATPase activity is indispensible in chemical-induced noncanonical autophagy

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中国药理学通报 2015年第B11期31卷 6-6页

作者： LIUYa-jun GAOYing LIUPei-qing LIMin NationalandLocalUnitedEngineeringLabofDruggabilityandNewDrugsEcaluation SchoolofPharmaceuticalSciencesSunYat-SenUniversitySchoolofPharmaceuticalSciencesGuangzhou510006

Autophagy is a highly evolutionarily conserved pathway that depends on lysosome to degrade misfolded proteins and damaged organelles. Besides canonical autophagy, studies have shown some chemicals could bypass several core genes to induce autophagy, but the targets and regulatory mechanism is still unclear. In this work one novel chemical, G1, was screened out which could trigger both canonical autophagy and non-canonical autophagy by recruiting Atgl6L1 to pre-autophagosomal site and causing LC3 lipidation. The Gl-induced non-canonical auto- phagy was ULK1, and Beclinl-independent but ubiquitin-like conjugation system-dependent, indicating G1 might target the upstream of Atgl6L1. Moreover, inhibition of V-ATPase by specific V-ATPase inhibitiors could suppress the formation of Gl-indueed autophagosomes in FIP200-defieient MEF cells. While other classic lysosomal inhibi- tors could not block the puneta of Atgl2, Atgl6L1 and LC3, in different stages, suggesting V-ATPase activity in- stead of lysosome function is required for Gl-indueed non-canonical autophagy. These studies broaden the under- standing of different working pattern of autophagy and the crucial roles of V-ATPase in the regulation of different au- tophagy.

关键词： autophgy non-canonical autophagy Ulkl complex Beclinl complex V-ATPase

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