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Prior SARS-CoV-2 infection rescues B and T cell responses to variants after first vaccine dose 期刊论文
Science, 2021
作者:  Catherine J. Reynolds;  Corinna Pade;  Joseph M. Gibbons;  David K. Butler;  Ashley D. Otter;  Katia Menacho;  Marianna Fontana;  Angelique Smit;  Jane E. Sackville-West;  Teresa Cutino-Moguel;  Mala K. Maini;  Benjamin Chain;  Mahdad Noursadeghi;  UK COVIDsortium Immune Correlates Network‡;  Tim Brooks;  Amanda Semper;  Charlotte Manisty;  Thomas A. Treibel;  James C. Moon;  UK COVIDsortium Investigators‡;  Ana M. Valdes;  Áine McKnight;  Daniel M. Altmann;  Rosemary Boyton
收藏  |  浏览/下载:10/0  |  提交时间:2021/07/27
Extensive heterogeneity in somatic mutation and selection in the human bladder 期刊论文
Science, 2020
作者:  Andrew R. J. Lawson;  Federico Abascal;  Tim H. H. Coorens;  Yvette Hooks;  Laura O’Neill;  Calli Latimer;  Keiran Raine;  Mathijs A. Sanders;  Anne Y. Warren;  Krishnaa T. A. Mahbubani;  Bethany Bareham;  Timothy M. Butler;  Luke M. R. Harvey;  Alex Cagan;  Andrew Menzies;  Luiza Moore;  Alexandra J. Colquhoun;  William Turner;  Benjamin Thomas;  Vincent Gnanapragasam;  Nicholas Williams;  Doris M. Rassl;  Harald Vöhringer;  Sonia Zumalave;  Jyoti Nangalia;  José M. C. Tubío;  Moritz Gerstung;  Kourosh Saeb-Parsy;  Michael R. Stratton;  Peter J. Campbell;  Thomas J. Mitchell;  Iñigo Martincorena
收藏  |  浏览/下载:19/0  |  提交时间:2020/10/12
Attribution of ground-level ozone to anthropogenic and natural sources of NOx and reactive carbon in a global chemical transport model 期刊论文
Atmospheric Chemistry and Physics, 2020
作者:  Tim Butler, Aurelia Lupascu, and Aditya Nalam
收藏  |  浏览/下载:15/0  |  提交时间:2020/05/25
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:16/0  |  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.


  
Femtosecond-to-millisecond structural changes in a light-driven sodium pump 期刊论文
NATURE, 2020, 583 (7815) : 314-+
作者:  Moore, Luiza;  Leongamornlert, Daniel;  Coorens, Tim H. H.;  Sanders, Mathijs A.;  Ellis, Peter;  Dentro, Stefan C.;  Dawson, Kevin J.;  Butler, Tim;  Rahbari, Raheleh;  Mitchell, Thomas J.;  Maura, Francesco;  Nangalia, Jyoti;  Tarpey, Patrick S.;  Brunner, Simon F.;  Lee-Six, Henry;  Hooks, Yvette;  Moody, Sarah;  Mahbubani, Krishnaa T.;  Jimenez-Linan, Mercedes;  Brosens, Jan J.;  Iacobuzio-Donahue, Christine A.;  Martincorena, Inigo;  Saeb-Parsy, Kourosh;  Campbell, Peter J.;  Stratton, Michael R.
收藏  |  浏览/下载:17/0  |  提交时间:2020/07/03

Light-driven sodium pumps actively transport small cations across cellular membranes(1). These pumps are used by microorganisms to convert light into membrane potential and have become useful optogenetic tools with applications in neuroscience. Although the resting state structures of the prototypical sodium pump Krokinobacter eikastus rhodopsin 2 (KR2) have been solved(2,3), it is unclear how structural alterations overtime allow sodium to be translocated against a concentration gradient. Here, using the Swiss X-ray Free Electron Laser(4), we have collected serial crystallographic data at ten pump-probe delays from femtoseconds to milliseconds. High-resolution structural snapshots throughout the KR2 photocycle show how retinal isomerization is completed on the femtosecond timescale and changes the local structure of the binding pocket in the early nanoseconds. Subsequent rearrangements and deprotonation of the retinal Schiff base open an electrostatic gate in microseconds. Structural and spectroscopic data, in combination with quantum chemical calculations, indicate that a sodium ion bind stransiently close to the retinal within one millisecond. In the last structural intermediate, at 20 milliseconds after activation, we identified a potential second sodium-binding site close to the extracellular exit. These results provide direct molecular insight into the dynamics of active cation transport across biological membranes.


  
Two conserved epigenetic regulators prevent healthy ageing 期刊论文
NATURE, 2020
作者:  Yoshida, Kenichi;  Gowers, Kate H. C.;  Lee-Six, Henry;  Chandrasekharan, Deepak P.;  Coorens, Tim;  Maughan, Elizabeth F.;  Beal, Kathryn;  Menzies, Andrew;  Millar, Fraser R.;  Anderson, Elizabeth;  Clarke, Sarah E.;  Pennycuick, Adam;  Thakrar, Ricky M.;  Butler, Colin R.;  Kakiuchi, Nobuyuki;  Hirano, Tomonori;  Hynds, Robert E.;  Stratton, Michael R.;  Martincorena, Inigo;  Janes, Sam M.;  Campbell, Peter J.
收藏  |  浏览/下载:34/0  |  提交时间:2020/07/03

It has long been assumed that lifespan and healthspan correlate strongly, yet the two can be clearly dissociated(1-6). Although there has been a global increase in human life expectancy, increasing longevity is rarely accompanied by an extended healthspan(4,7). Thus, understanding the origin of healthy behaviours in old people remains an important and challenging task. Here we report a conserved epigenetic mechanism underlying healthy ageing. Through genome-wide RNA-interference-based screening of genes that regulate behavioural deterioration in ageing Caenorhabditis elegans, we identify 59 genes as potential modulators of the rate of age-related behavioural deterioration. Among these modulators, we found that a neuronal epigenetic reader, BAZ-2, and a neuronal histone 3 lysine 9 methyltransferase, SET-6, accelerate behavioural deterioration in C. elegans by reducing mitochondrial function, repressing the expression of nuclear-encoded mitochondrial proteins. This mechanism is conserved in cultured mouse neurons and human cells. Examination of human databases(8,9) shows that expression of the human orthologues of these C. elegans regulators, BAZ2B and EHMT1, in the frontal cortex increases with age and correlates positively with the progression of Alzheimer'  s disease. Furthermore, ablation of Baz2b, the mouse orthologue of BAZ-2, attenuates age-dependent body-weight gain and prevents cognitive decline in ageing mice. Thus our genome-wide RNA-interference screen in C. elegans has unravelled conserved epigenetic negative regulators of ageing, suggesting possible ways to achieve healthy ageing.


Two epigenetic regulators-identified in an RNA interference screen in Caenhorhabditis elegans, and conserved in mammals-diminish mitochondrial function and accelerate the age-related deterioration of behaviour.


  
High-pressure strengthening in ultrafine-grained metals 期刊论文
NATURE, 2020
作者:  Yoshida, Kenichi;  Gowers, Kate H. C.;  Lee-Six, Henry;  Chandrasekharan, Deepak P.;  Coorens, Tim;  Maughan, Elizabeth F.;  Beal, Kathryn;  Menzies, Andrew;  Millar, Fraser R.;  Anderson, Elizabeth;  Clarke, Sarah E.;  Pennycuick, Adam;  Thakrar, Ricky M.;  Butler, Colin R.
收藏  |  浏览/下载:25/0  |  提交时间:2020/07/03

High-pressure diamond anvil cell experiments reveal that compression strengthening of nanocrystalline nickel increases as its grain sizes decrease to 3 nanometres, owing to dislocation hardening and suppression of grain boundary plasticity.


The Hall-Petch relationship, according to which the strength of a metal increases as the grain size decreases, has been reported to break down at a critical grain size of around 10 to 15 nanometres(1,2). As the grain size decreases beyond this point, the dominant mechanism of deformation switches from a dislocation-mediated process to grain boundary sliding, leading to material softening. In one previous approach, stabilization of grain boundaries through relaxation and molybdenum segregation was used to prevent this softening effect in nickel-molybdenum alloys with grain sizes below 10 nanometres(3). Here we track in situ the yield stress and deformation texturing of pure nickel samples of various average grain sizes using a diamond anvil cell coupled with radial X-ray diffraction. Our high-pressure experiments reveal continuous strengthening in samples with grain sizes from 200 nanometres down to 3 nanometres, with the strengthening enhanced (rather than reduced) at grain sizes smaller than 20 nanometres. We achieve a yield strength of approximately 4.2 gigapascals in our 3-nanometre-grain-size samples, ten times stronger than that of a commercial nickel material. A maximum flow stress of 10.2 gigapascals is obtained in nickel of grain size 3 nanometres for the pressure range studied here. We see similar patterns of compression strengthening in gold and palladium samples down to the smallest grain sizes. Simulations and transmission electron microscopy reveal that the high strength observed in nickel of grain size 3 nanometres is caused by the superposition of strengthening mechanisms: both partial and full dislocation hardening plus suppression of grain boundary plasticity. These insights contribute to the ongoing search for ultrastrong metals via materials engineering.


  
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.


  
Source attribution of European surface O-3 using a tagged O-3 mechanism 期刊论文
ATMOSPHERIC CHEMISTRY AND PHYSICS, 2019, 19 (23) : 14535-14558
作者:  Lupascu, Aurelia;  Butler, Tim
收藏  |  浏览/下载:5/0  |  提交时间:2020/02/17
Global assessment of agricultural system redesign for sustainable intensification 期刊论文
NATURE SUSTAINABILITY, 2018, 1 (8) : 441-446
作者:  Pretty, Jules;  Benton, Tim G.;  Bharucha, Zareen Pervez;  Dicks, Lynn V.;  Flora, Cornelia Butler;  Godfray, H. Charles J.;  Goulson, Dave;  Hartley, Sue;  Lampkin, Nic;  Morris, Carol;  Pierzynski, Gary;  Prasad, P. V. Vara;  Reganold, John;  Rockstrom, Johan;  Smith, Pete;  Thorne, Peter;  Wratten, Steve
收藏  |  浏览/下载:6/0  |  提交时间:2020/08/19