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CRISPR screen in regulatory T cells reveals modulators of Foxp3 期刊论文
NATURE, 2020
作者:  Xu, Daqian;  Wang, Zheng;  Xia, Yan;  Shao, Fei;  Xia, Weiya;  Wei, Yongkun;  Li, Xinjian;  Qian, Xu;  Lee, Jong-Ho;  Du, Linyong;  Zheng, Yanhua;  Lv, Guishuai;  Leu, Jia-shiun;  Wang, Hongyang;  Xing, Dongming;  Liang, Tingbo;  Hung, Mien-Chie;  Lu, Zhimin
收藏  |  浏览/下载:49/0  |  提交时间:2020/07/03

Regulatory T (T-reg) cells are required to control immune responses and maintain homeostasis, but are a significant barrier to antitumour immunity(1). Conversely, T-reg instability, characterized by loss of the master transcription factor Foxp3 and acquisition of proinflammatory properties(2), can promote autoimmunity and/or facilitate more effective tumour immunity(3,4). A comprehensive understanding of the pathways that regulate Foxp3 could lead to more effective T-reg therapies for autoimmune disease and cancer. The availability of new functional genetic tools has enabled the possibility of systematic dissection of the gene regulatory programs that modulate Foxp3 expression. Here we developed a CRISPR-based pooled screening platform for phenotypes in primary mouse T-reg cells and applied this technology to perform a targeted loss-of-function screen of around 500 nuclear factors to identify gene regulatory programs that promote or disrupt Foxp3 expression. We identified several modulators of Foxp3 expression, including ubiquitin-specific peptidase 22 (Usp22) and ring finger protein 20 (Rnf20). Usp22, a member of the deubiquitination module of the SAGA chromatin-modifying complex, was revealed to be a positive regulator that stabilized Foxp3 expression  whereas the screen suggested that Rnf20, an E3 ubiquitin ligase, can serve as a negative regulator of Foxp3. T-reg-specific ablation of Usp22 in mice reduced Foxp3 protein levels and caused defects in their suppressive function that led to spontaneous autoimmunity but protected against tumour growth in multiple cancer models. Foxp3 destabilization in Usp22-deficient T-reg cells could be rescued by ablation of Rnf20, revealing a reciprocal ubiquitin switch in T-reg cells. These results reveal previously unknown modulators of Foxp3 and demonstrate a screening method that can be broadly applied to discover new targets for T-reg immunotherapies for cancer and autoimmune disease.


A CRISPR-based screening platform was used to identify previously uncharacterized genes that regulate the regulatory T cell-specific master transcription factor Foxp3, indicating that this screening method may be broadly applicable for the discovery of other genes involved in autoimmunity and immune responses to cancer.


  
Variability in the analysis of a single neuroimaging dataset by many teams 期刊论文
NATURE, 2020
作者:  Liu, Jifeng;  Soria, Roberto;  Zheng, Zheng;  Zhang, Haotong;  Lu, Youjun;  Wang, Song;  Yuan, Hailong
收藏  |  浏览/下载:38/0  |  提交时间:2020/07/03

Data analysis workflows in many scientific domains have become increasingly complex and flexible. Here we assess the effect of this flexibility on the results of functional magnetic resonance imaging by asking 70 independent teams to analyse the same dataset, testing the same 9 ex-ante hypotheses(1). The flexibility of analytical approaches is exemplified by the fact that no two teams chose identical workflows to analyse the data. This flexibility resulted in sizeable variation in the results of hypothesis tests, even for teams whose statistical maps were highly correlated at intermediate stages of the analysis pipeline. Variation in reported results was related to several aspects of analysis methodology. Notably, a meta-analytical approach that aggregated information across teams yielded a significant consensus in activated regions. Furthermore, prediction markets of researchers in the field revealed an overestimation of the likelihood of significant findings, even by researchers with direct knowledge of the dataset(2-5). Our findings show that analytical flexibility can have substantial effects on scientific conclusions, and identify factors that may be related to variability in the analysis of functional magnetic resonance imaging. The results emphasize the importance of validating and sharing complex analysis workflows, and demonstrate the need for performing and reporting multiple analyses of the same data. Potential approaches that could be used to mitigate issues related to analytical variability are discussed.


The results obtained by seventy different teams analysing the same functional magnetic resonance imaging dataset show substantial variation, highlighting the influence of analytical choices and the importance of sharing workflows publicly and performing multiple analyses.


  
Coming at cancer from all angles 期刊论文
NATURE, 2020, 580 (7804) : S24-S27
作者:  Ghasemi, Ali;  De Palma, Michele
收藏  |  浏览/下载:8/0  |  提交时间:2020/07/03

The search for disease mechanisms and treatments is one of the biggest collaborative efforts in science. These researchers are significant contributors.


The search for disease mechanisms and treatments is one of the biggest collaborative efforts in science. These researchers are significant contributors.


  
Effect of lower stratospheric temperature on total ozone column (TOC) during the ozone depletion and recovery phases 期刊论文
ATMOSPHERIC RESEARCH, 2020, 232
作者:  Ningombam, Shantikumar S.;  Vemareddy, P.;  Song, H-J
收藏  |  浏览/下载:10/0  |  提交时间:2020/07/02
Total ozone column  Equivalent Effective Stratospheric Chlorine  Back-scatter ultraviolet  Statistically significant  
Observational and modelling evidence of a zonal circulation over the North Pacific 期刊论文
INTERNATIONAL JOURNAL OF CLIMATOLOGY, 2019
作者:  Zou, Youjia;  Xi, Xiangying
收藏  |  浏览/下载:31/0  |  提交时间:2020/02/17
NH climate change  North Pacific  significant impact  thermal driving  zonal overturning circulation cell  
Long-term cyclic persistence in an experimental predator-prey system 期刊论文
NATURE, 2020, 577 (7789) : 226-+
作者:  Blasius, Bernd;  Rudolf, Lars;  Weithoff, Guntram;  Gaedke, Ursula;  Fussmann, Gregor F.
收藏  |  浏览/下载:27/0  |  提交时间:2020/04/16

Predator-prey cycles rank among the most fundamental concepts in ecology, are predicted by the simplest ecological models and enable, theoretically, the indefinite persistence of predator and prey(1-4). However, it remains an open question for how long cyclic dynamics can be self-sustained in real communities. Field observations have been restricted to a few cycle periods(5-8) and experimental studies indicate that oscillations may be short-lived without external stabilizing factors(9-19). Here we performed microcosm experiments with a planktonic predator-prey system and repeatedly observed oscillatory time series of unprecedented length that persisted for up to around 50 cycles or approximately 300 predator generations. The dominant type of dynamics was characterized by regular, coherent oscillations with a nearly constant predator-prey phase difference. Despite constant experimental conditions, we also observed shorter episodes of irregular, non-coherent oscillations without any significant phase relationship. However, the predator-prey system showed a strong tendency to return to the dominant dynamical regime with a defined phase relationship. A mathematical model suggests that stochasticity is probably responsible for the reversible shift from coherent to non-coherent oscillations, a notion that was supported by experiments with external forcing by pulsed nutrient supply. Our findings empirically demonstrate the potential for infinite persistence of predator and prey populations in a cyclic dynamic regime that shows resilience in the presence of stochastic events.


  
Deterministic Skill of Subseasonal Precipitation Forecasts for the East Africa-West Asia Sector from September to May 期刊论文
JOURNAL OF GEOPHYSICAL RESEARCH-ATMOSPHERES, 2019, 124 (22) : 11887-11896
作者:  Vigaud, N.;  Tippett, M. K.;  Robertson, A. W.
收藏  |  浏览/下载:22/0  |  提交时间:2020/02/17
S2S rainfall forecasts show statistically significant skill in the East Africa-West Asia sector out to Week 4  Forecast skill of dynamical models exceeds that of statistical models based on ENSO and the MJO  Tropical-temperate interactions may represent a new source of S2S predictability  
On the generation and propagation of Makran swells in the Arabian Sea 期刊论文
INTERNATIONAL JOURNAL OF CLIMATOLOGY, 2019
作者:  Anoop, Thondithala R.;  Shanas, Puthuveetil R.;  Aboobacker, Valliyil M.;  Kumar, V. Sanil;  Nair, Leela Sheela;  Prasad, Ravindran;  Reji, Srinivas
收藏  |  浏览/下载:27/0  |  提交时间:2019/11/27
Arabian Sea  low-level jet  Makran swells  monsoon  Shamal swells  significant wave height  
Significant Role of Orography in Shaping the Northern Hadley Circulation and Its Poleward Expansion During Boreal Summer 期刊论文
GEOPHYSICAL RESEARCH LETTERS, 2018, 45 (13) : 6619-6627
作者:  Cheng, Jianbo;  Xu, Zhihang;  Hu, Po;  Hou, Xiaoya;  Gao, Chenbin;  Hu, Shujuan;  Feng, Guolin
收藏  |  浏览/下载:19/0  |  提交时间:2019/04/09
minor circulation  significant role of orography  three different methods  Hadley circulation  poleward expansion  
Sea Surface Height Measurement Using a GNSS Wave Glider 期刊论文
GEOPHYSICAL RESEARCH LETTERS, 2018, 45 (11) : 5609-5616
作者:  Penna, Nigel T.;  Maqueda, Miguel A. Morales;  Martin, Ian;  Guo, Jing;  Foden, Peter R.
收藏  |  浏览/下载:11/0  |  提交时间:2019/04/09
Wave Glider  GNSS  sea surface height  dynamic ocean topography  geoid  significant wave height