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| 1 | Improving Plant Genome Editing with High-Fidelity xCas9 and Non-canonical PAM-Targeting Cas9-NG显示文摘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. | 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 | 2019 | Molecular Plant2019，12，7： | 13 |
| 2 | A durable 4-1BB-based CD19 CAR-T cell for treatment of relapsed or refractory non-Hodgkin lymphoma显示文摘Objective:Previous studies reported that 4-1BB-based CD19 chimeric antigen receptor(CAR)-T cells were more beneficial for the clinical outcomes than CD28-based CAR-T cells,especially the lower incidence rate of severe adverse events.However,the median progression-free survival(mPFS)of 4-1BB-based product Kymriah was shorter than that of CD28-based Yescarta(2.9 months vs.5.9 months),suggesting that Kymriah was limited in the long-term efficacy.Thus,a safe and durable 4-1BB-based CD19 CAR-T needs to be developed.Methods:We designed a CD19-targeted CAR-T(named as IM19)which consisted of an FMC63 scFv,4-1BB and CD3ζintracellular domain and was manufactured into a memory T-enriched formulation.A phase I/II clinical trial was launched to evaluate the clinical outcomes of IM19 in relapsed or refractory(r/r)B cell non-Hodgkin lymphoma(B-NHL).Dose-escalation investigation(at a dose of 5×10^(5)/kg,1×10^(6)/kg and 3×106/kg)was performed in 22 r/r B-NHL patients.All patients received a single infusion of IM19 after 3-day conditional regimen.Results:At month 3,the overall response rate(ORR)was 59.1%,the complete response rate(CRR)was 50.0%.The mPFS was 6 months and the 1-year overall survival rate was 77.8%.Cytokine release syndrome(CRS)occurred in 13 patients(59.1%),with 54.5%of grade 1−2 CRS.Only one patient(4.5%)experienced grade 3 CRS and grade 3 neurotoxicity.Conclusions:These results demonstrated the safety and durable efficacy of a 4-1BB-based CD19 CAR-T,IM19,which is promising for further development and clinical investigation. | Zhitao Ying Ting He Shanzhao Jin Xiaopei Wang Wen Zheng Ningjing Lin Meifeng Tu Yan Xie Lingyan Ping Weiping Liu Lijuan Deng Yanping Ding Xuelian Hu Bing Bu Xin’an Lu Yuqin Song Jun Zhu | 2022 | Chinese Journal of Cancer Research2022，34，1： | 2 |
| 3 | Effect of defects and remediation measures on the internal forces caused by a local thickness reduction in the tunnel lining显示文摘This study presents a case history of a tunnel lining with an insufficient thickness.The effect of the defects resulting from the insuf-ficient thickness of the secondary lining and their locations on the internal forces are discussed based on numerical analysis.The results show that defects increase the number of inflection points in the defect region.The increased maximum bending moment is located on the air side of the secondary lining around the defect region.The defects near the crown of the secondary lining have the most significant influence on the internal forces of the primary and secondary linings,while the defects near the sidewall of the secondary lining have a limited influence on the internal forces of the lining.A remediation measure consisting of the installation of a tertiary lining is proposed and its efficiency is analyzed.The tertiary lining significantly reduces the bending moment of the secondary lining and the axial force of the primary lining.The effect of the thickness and location of the tertiary lining on the tunnel performance is discussed. | Ping Lu Dongwang Qiao Chunxiao Wu Shun Wang Xiaopei He Wenjun Zhang Haizuo Zhou | 2022 | Underground Space2022，7，1： | 1 |
| 4 | Co-variation of the surface wind speed and the sea surface temperature over mesoscale eddies in the Gulf Stream region:momentum vertical mixing aspect显示文摘The co-variation of surface wind speed and sea surface temperature (SST) over the Gulf Stream frontal region is investigated using high-resolution satellite measurements and atmospheric reanalysis data. Results show that the pattern of positive SST-surface wind speed correlations is anchored by strong SST gradient and marine atmospheric boundary layer (MABL) height front, with active warm and cold-ocean eddies around. The MABL has an obvious transitional structure along the strong SST front, with greater (lesser) heights over the north (south) side. The significant positive SST-surface wind-speed perturbation correlations are mostly found over both strong warm and cold eddies. The surface wind speed increases (decreases) about 0.32 (0.41) m/s and the MABL elevates (drops) approximate 55 (54) m per 1℃ of SST perturbation induced by warm (cold) eddies. The response of the surface wind speed to SST perturbations over the mesoscale eddies is mainly attributed to the momentum vertical mixing in the MABL, which is confirmed by the linear relationships between the downwind (crosswind) SST gradient and wind divergence (curl). | HE Jingjing LIN Xiaopei | 2019 | Journal of Oceanology and Limnology2019，37，4： | 0 |
| 5 | Seasonal response of surface wind to SST perturbation in the Northern Hemisphere显示文摘The seasonal response of surface wind speed to sea surface temperature (SST) change in the Northern Hemisphere was investigated using 10 years (2002-2011) high-resolution satellite observations and reanalysis data. The results showed that correlation between surface wind speed perturbations and SST perturbations exhibits remarkable seasonal variation, with more positive correlation is stronger in the cold seasons than in the warm seasons. This seasonality in a positive correlation between SST and surface wind speed is attributable primarily to seasonal changes of oceanic and atmospheric background conditions in frontal regions. The mean SST gradient and the prevailing surface winds are strong in winter and weak in summer. Additionally, the eddy-induced response of surface wind speed is stronger in winter than in summer, although the locations and numbers of mesoscale eddies do not show obvious seasonal features. The response of surface wind speed is apparently due to stability and mixing within the marine atmospheric boundary layer (MABL), modulated by SST perturbations. In the cold seasons, the stronger positive (negative) SST perturbations are easier to increase (decrease) the MABL height and trigger (suppress) momentum vertical mixing, contributing to the positive correlation between SST and surface wind speed. In comparison, SST perturbations are relatively weak in the warm seasons, resulting in a weak response of surface wind speed to SST changes. This result holds for each individual region with energetic eddy activity in the Northern Hemisphere. | HE Jingjing HAN Xueshuang LIN Xiaopei | 2019 | Journal of Oceanology and Limnology2019，37，4： | 0 |
| 6 | Quantitative Analysis of Mineralization-Alteration Index about the Huize Lead-zinc district in Northeast Yunnan, China显示文摘1 Introduction The super-large Huize lead-zinc ore district is one of the most representative lead-zinc deposits in Northeastern Yunnan poly-metallic deposit concentration district.So far,studies(Liu and Lin,1999;Han et al.,2007)on the type of deposits like the Huize lead-zinc deposit,focused on deposit genesis,the sources of metallogenic materials, | ZHANG Xiaopei HAN Runsheng ZHAO Dong QIU Wenlong HE Jiaojiao CUI Junhao | 2017 | Acta Geologica Sinica(English Edition)2017，91，S1： | 0 |
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