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HBO1 is required for the maintenance of leukaemia stem cells 期刊论文
NATURE, 2020, 577 (7789) : 266-+
作者:  MacPherson, Laura;  Anokye, Juliana;  Yeung, Miriam M.;  Lam, Enid Y. N.;  Chan, Yih-Chih;  Weng, Chen-Fang;  Yeh, Paul;  Knezevic, Kathy;  Butler, Miriam S.;  Hoegl, Annabelle;  Chan, Kah-Lok;  Burr, Marian L.;  Gearing, Linden J.;  Willson, Tracy;  Liu, Joy;  Choi, Jarny;  Yang, Yuqing;  Bilardi, Rebecca A.;  Falk, Hendrik;  Nghi Nguyen;  Stupple, Paul A.;  Peat, Thomas S.;  Zhang, Ming;  de Silva, Melanie;  Carrasco-Pozo, Catalina;  Avery, Vicky M.;  Khoo, Poh Sim;  Dolezal, Olan;  Dennis, Matthew L.;  Nuttall, Stewart;  Surjadi, Regina;  Newman, Janet;  Ren, Bin;  Leaver, David J.;  Sun, Yuxin;  Baell, Jonathan B.;  Dovey, Oliver;  Vassiliou, George S.;  Grebien, Florian;  Dawson, Sarah-Jane;  Street, Ian P.;  Monahan, Brendon J.;  Burns, Christopher J.;  Choudhary, Chunaram;  Blewitt, Marnie E.;  Voss, Anne K.;  Thomas, Tim;  Dawson, Mark A.
收藏  |  浏览/下载:17/0  |  提交时间:2020/07/03

Acute myeloid leukaemia (AML) is a heterogeneous disease characterized by transcriptional dysregulation that results in a block in differentiation and increased malignant self-renewal. Various epigenetic therapies aimed at reversing these hallmarks of AML have progressed into clinical trials, but most show only modest efficacy owing to an inability to effectively eradicate leukaemia stem cells (LSCs)(1). Here, to specifically identify novel dependencies in LSCs, we screened a bespoke library of small hairpin RNAs that target chromatin regulators in a unique ex vivo mouse model of LSCs. We identify the MYST acetyltransferase HBO1 (also known as KAT7 or MYST2) and several known members of the HBO1 protein complex as critical regulators of LSC maintenance. Using CRISPR domain screening and quantitative mass spectrometry, we identified the histone acetyltransferase domain of HBO1 as being essential in the acetylation of histone H3 at K14. H3 acetylated at K14 (H3K14ac) facilitates the processivity of RNA polymerase II to maintain the high expression of key genes (including Hoxa9 and Hoxa10) that help to sustain the functional properties of LSCs. To leverage this dependency therapeutically, we developed a highly potent small-molecule inhibitor of HBO1 and demonstrate its mode of activity as a competitive analogue of acetyl-CoA. Inhibition of HBO1 phenocopied our genetic data and showed efficacy in a broad range of human cell lines and primary AML cells from patients. These biological, structural and chemical insights into a therapeutic target in AML will enable the clinical translation of these findings.


  
The fate of carbon in a mature forest under carbon dioxide enrichment 期刊论文
NATURE, 2020, 580 (7802) : 227-+
作者:  Sun, P. Z.;  Yang, Q.;  Kuang, W. J.;  Stebunov, Y. V.;  Xiong, W. Q.;  Yu, J.;  Nair, R. R.;  Katsnelson, M. I.;  Yuan, S. J.;  Grigorieva, I. V.;  Lozada-Hidalgo, M.;  Wang, F. C.;  Geim, A. K.
收藏  |  浏览/下载:70/0  |  提交时间:2020/05/13

Carbon dioxide enrichment of a mature forest resulted in the emission of the excess carbon back into the atmosphere via enhanced ecosystem respiration, suggesting that mature forests may be limited in their capacity to mitigate climate change.


Atmospheric carbon dioxide enrichment (eCO(2)) can enhance plant carbon uptake and growth(1-5), thereby providing an important negative feedback to climate change by slowing the rate of increase of the atmospheric CO2 concentration(6). Although evidence gathered from young aggrading forests has generally indicated a strong CO2 fertilization effect on biomass growth(3-5), it is unclear whether mature forests respond to eCO(2) in a similar way. In mature trees and forest stands(7-10), photosynthetic uptake has been found to increase under eCO(2) without any apparent accompanying growth response, leaving the fate of additional carbon fixed under eCO(2) unclear(4,5,7-11). Here using data from the first ecosystem-scale Free-Air CO2 Enrichment (FACE) experiment in a mature forest, we constructed a comprehensive ecosystem carbon budget to track the fate of carbon as the forest responded to four years of eCO(2) exposure. We show that, although the eCO(2) treatment of +150 parts per million (+38 per cent) above ambient levels induced a 12 per cent (+247 grams of carbon per square metre per year) increase in carbon uptake through gross primary production, this additional carbon uptake did not lead to increased carbon sequestration at the ecosystem level. Instead, the majority of the extra carbon was emitted back into the atmosphere via several respiratory fluxes, with increased soil respiration alone accounting for half of the total uptake surplus. Our results call into question the predominant thinking that the capacity of forests to act as carbon sinks will be generally enhanced under eCO(2), and challenge the efficacy of climate mitigation strategies that rely on ubiquitous CO2 fertilization as a driver of increased carbon sinks in global forests.


  
Mechanical regulation of glycolysis via cytoskeleton architecture 期刊论文
NATURE, 2020, 578 (7796) : 621-+
作者:  Faivre, Emily J.;  McDaniel, Keith F.;  Albert, Daniel H.;  Mantena, Srinivasa R.;  Plotnik, Joshua P.;  Wilcox, Denise;  Zhang, Lu;  Bui, Mai H.;  Sheppard, George S.;  Wang, Le;  Sehgal, Vasudha;  Lin, Xiaoyu;  Huang, Xiaoli;  Lu, Xin;  Uziel, Tamar;  Hessler, Paul;  Lam, Lloyd T.;  Bellin, Richard J.;  Mehta, Gaurav;  Fidanze, Steve;  Pratt, John K.;  Liu, Dachun;  Hasvold, Lisa A.;  Sun, Chaohong;  Panchal, Sanjay C.;  Nicolette, John J.;  Fossey, Stacey L.;  Park, Chang H.;  Longenecker, Kenton;  Bigelow, Lance;  Torrent, Maricel;  Rosenberg, Saul H.;  Kati, Warren M.;  Shen, Yu
收藏  |  浏览/下载:15/0  |  提交时间:2020/07/03

The mechanics of the cellular microenvironment continuously modulates cell functions such as growth, survival, apoptosis, differentiation and morphogenesis via cytoskeletal remodelling and actomyosin contractility(1-3). Although all of these processes consume energy(4,5), it is unknown whether and how cells adapt their metabolic activity to variable mechanical cues. Here we report that the transfer of human bronchial epithelial cells from stiff to soft substrates causes a downregulation of glycolysis via proteasomal degradation of the rate-limiting metabolic enzyme phosphofructokinase (PFK). PFK degradation is triggered by the disassembly of stress fibres, which releases the PFK-targeting E3 ubiquitin ligase tripartite motif (TRIM)-containing protein 21 (TRIM21). Transformed non-small-cell lung cancer cells, which maintain high glycolytic rates regardless of changing environmental mechanics, retain PFK expression by downregulating TRIM21, and by sequestering residual TRIM21 on a stress-fibre subset that is insensitive to substrate stiffness. Our data reveal a mechanism by which glycolysis responds to architectural features of the actomyosin cytoskeleton, thus coupling cell metabolism to the mechanical properties of the surrounding tissue. These processes enable normal cells to tune energy production in variable microenvironments, whereas the resistance of the cytoskeleton in response to mechanical cues enables the persistence of high glycolytic rates in cancer cells despite constant alterations of the tumour tissue.


Glycolysis in normal epithelial cells responds to microenvironmental mechanics via the modulation of actin bundles that sequester the phosphofructokinase-targeting ubiquitin ligase TRIM21, a process superseded by persistent actin bundles in cancer cells.


  
Signatures of self-organized criticality in an ultracold atomic gas 期刊论文
NATURE, 2020, 577 (7791) : 481-+
作者:  MacPherson, Laura;  Anokye, Juliana;  Yeung, Miriam M.;  Lam, Enid Y. N.;  Chan, Yih-Chih;  Weng, Chen-Fang;  Yeh, Paul;  Knezevic, Kathy;  Butler, Miriam S.;  Hoegl, Annabelle;  Chan, Kah-Lok;  Burr, Marian L.;  Gearing, Linden J.;  Willson, Tracy;  Liu, Joy;  Choi, Jarny;  Yang, Yuqing;  Bilardi, Rebecca A.;  Falk, Hendrik;  Nghi Nguyen;  Stupple, Paul A.;  Peat, Thomas S.;  Zhang, Ming;  De Silva, Melanie;  Carrasco-Pozo, Catalina;  Avery, Vicky M.;  Khoo, Sim;  Dolezal, Olan;  Dennis, Matthew L.;  Nuttall, Stewart;  Surjadi, Regina;  Newman, Janet;  Ren, Bin;  Leaver, David J.;  Sun, Yuxin;  Baell, Jonathan B.;  Dovey, Oliver;  Vassiliou, George S.;  Grebien, Florian;  Dawson, Sarah-Jane;  Street, Ian P.;  Monahan, Brendon J.;  Burns, Christopher J.;  Choudhary, Chunaram;  Blewitt, Marnie E.;  Voss, Anne K.;  Thomas, Tim;  Dawson, Mark A.
收藏  |  浏览/下载:24/0  |  提交时间:2020/07/03

Self-organized criticality is an elegant explanation of how complex structures emerge and persist throughout nature(1), and why such structures often exhibit similar scale-invariant properties(2-9). Although self-organized criticality is sometimes captured by simple models that feature a critical point as an attractor for the dynamics(10-15), the connection to real-world systems is exceptionally hard to test quantitatively(16-21). Here we observe three key signatures of self-organized criticality in the dynamics of a driven-dissipative gas of ultracold potassium atoms: self-organization to a stationary state that is largely independent of the initial conditions  scale-invariance of the final density characterized by a unique scaling function  and large fluctuations of the number of excited atoms (avalanches) obeying a characteristic power-law distribution. This work establishes a well-controlled platform for investigating self-organization phenomena and non-equilibrium criticality, with experimental access to the underlying microscopic details of the system.


A driven-dissipative gas of ultracold potassium atoms is used to demonstrate three key signatures of self-organized criticality, and provides a system in which the phenomenon can be experimentally tested.


  
Human origins in a southern African palaeo-wetland and first migrations 期刊论文
Nature, 2019, 575: 185-189
作者:  Eva K. F. Chan;  Axel Timmermann;  Benedetta F. Baldi;  Andy E. Moore;  Ruth J. Lyons;  Sun-Seon Lee;  Anton M. F. Kalsbeek;  Desiree C. Petersen;  Hannes Rautenbach;  Hagen E. A. F枚rtsch;  M. S. Riana Bornman;  Vanessa M. Hayes
收藏  |  浏览/下载:8/0  |  提交时间:2019/11/27
Magnetic Weyl semimetal phase in a Kagome crystal 期刊论文
SCIENCE, 2019, 365 (6459) : 1282-+
作者:  Liu, D. F.;  Liang, A. J.;  Liu, E. K.;  Xu, Q. N.;  Li, Y. W.;  Chen, C.;  Pei, D.;  Shi, W. J.;  Mo, S. K.;  Dudin, P.;  Kim, T.;  Cacho, C.;  Li, G.;  Sun, Y.;  Yang, L. X.;  Liu, Z. K.;  Parkin, S. S. P.;  Felser, C.;  Chen, Y. L.
收藏  |  浏览/下载:10/0  |  提交时间:2019/11/27
A pharmacological master key mechanism that unlocks the selectivity filter gate in K+ channels 期刊论文
SCIENCE, 2019, 363 (6429) : 875-+
作者:  Schewe, Marcus;  Sun, Han;  Mert, Umit;  Mackenzie, Alexandra;  Pike, Ashley C. W.;  Schulz, Friederike;  Constantin, Cristina;  Vowinkel, Kirsty S.;  Conrad, Linus J.;  Kiper, Aytug K.;  Gonzalez, Wendy;  Musinszki, Marianne;  Tegtmeier, Marie;  Pryde, David C.;  Belabed, Hassane;  Nazare, Marc;  de Groot, Bert L.;  Decher, Niels;  Fakler, Bernd;  Carpenter, Elisabeth P.;  Tucker, Stephen J.;  Baukrowitz, Thomas
收藏  |  浏览/下载:5/0  |  提交时间:2019/11/27
Coupling between surface ozone and leaf area index in a chemical transport model: strength of feedback and implications for ozone air quality and vegetation health 期刊论文
ATMOSPHERIC CHEMISTRY AND PHYSICS, 2018, 18 (19) : 14133-14148
作者:  Zhou, Shan S.;  Tai, Amos P. K.;  Sun, Shihan;  Sadiq, Mehliyar;  Heald, Colette L.;  Geddes, Jeffrey A.
收藏  |  浏览/下载:6/0  |  提交时间:2019/04/09
Rapid transition from continental breakup to igneous oceanic crust in the South China Sea 期刊论文
NATURE GEOSCIENCE, 2018, 11 (10) : 782-+
作者:  Larsen, H. C.;  Mohn, G.;  Nirrengarten, M.;  Sun, Z.;  Stock, J.;  Jian, Z.;  Klaus, A.;  Alvarez-Zarikian, C. A.;  Boaga, J.;  Bowden, S. A.;  Briais, A.;  Chen, Y.;  Cukur, D.;  Dadd, K.;  Ding, W.;  Dorais, M.;  Ferre, E. C.;  Ferreira, F.;  Furusawa, A.;  Gewecke, A.;  Hinojosa, J.;  Hofig, T. W.;  Hsiung, K. H.;  Huang, B.;  Huang, E.;  Huang, X. L.;  Jiang, S.;  Jin, H.;  Johnson, B. G.;  Kurzawski, R. M.;  Lei, C.;  Li, B.;  Li, L.;  Li, Y.;  Lin, J.;  Liu, C.;  Liu, Z.;  Luna, A. J.;  Lupi, C.;  McCarthy, A.;  Ningthoujam, L.;  Osono, N.;  Peate, D. W.;  Persaud, P.;  Qiu, N.;  Robinson, C.;  Satolli, S.;  Sauermilch, I;  Schindlbeck, J. C.;  Skinner, S.;  Straub, S.;  Su, X.;  Su, C.;  Tian, L.;  Van Der Zwan, F. M.;  Wan, S.;  Wu, H.;  Xiang, R.;  Yadav, R.;  Yi, L.;  Yu, P. S.;  Zhang, C.;  Zhang, J.;  Zhang, Y.;  Zhao, N.;  Zhong, G.;  Zhong, L.
收藏  |  浏览/下载:13/0  |  提交时间:2019/04/09
Multi-model study of HTAP II on sulfur and nitrogen deposition 期刊论文
ATMOSPHERIC CHEMISTRY AND PHYSICS, 2018, 18 (9) : 6847-6866
作者:  Tan, Jiani;  Fu, Joshua S.;  Dentener, Frank;  Sun, Jian;  Emmons, Louisa;  Tilmes, Simone;  Sudo, Kengo;  Flemming, Johannes;  Jonson, Jan Eiof;  Gravel, Sylvie;  Bian, Huisheng;  Davila, Yanko;  Henze, Daven K.;  Lund, Marianne T.;  Kucsera, Tom;  Takemura, Toshihiko;  Keating, Terry
收藏  |  浏览/下载:10/0  |  提交时间:2019/04/09