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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:20/0  |  提交时间:2020/10/12
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.


  
Ice front blocking of ocean heat transport to an Antarctic ice shelf 期刊论文
NATURE, 2020, 578 (7796) : 568-+
作者:  Alexandrov, Ludmil B.;  Kim, Jaegil;  Haradhvala, Nicholas J.;  Huang, Mi Ni;  Ng, Alvin Wei Tian;  Wu, Yang;  Boot, Arnoud;  Covington, Kyle R.;  Gordenin, Dmitry A.;  Bergstrom, Erik N.;  Islam, S. M. Ashiqul;  Lopez-Bigas, Nuria;  Klimczak, Leszek J.;  McPherson, John R.;  Morganella, Sandro;  Sabarinathan, Radhakrishnan;  Wheeler, David A.;  Mustonen, Ville;  Getz, Gad;  Rozen, Steven G.;  Stratton, Michael R.
收藏  |  浏览/下载:12/0  |  提交时间:2020/05/13

The front of the Getz Ice Shelf in West Antarctica creates an abrupt topographic step that deflects ocean currents, suppressing 70% of the heat delivery to the ice sheet.


Mass loss from the Antarctic Ice Sheet to the ocean has increased in recent decades, largely because the thinning of its floating ice shelves has allowed the outflow of grounded ice to accelerate(1,2). Enhanced basal melting of the ice shelves is thought to be the ultimate driver of change(2,3), motivating a recent focus on the processes that control ocean heat transport onto and across the seabed of the Antarctic continental shelf towards the ice(4-6). However, the shoreward heat flux typically far exceeds that required to match observed melt rates(2,7,8), suggesting that other critical controls exist. Here we show that the depth-independent (barotropic) component of the heat flow towards an ice shelf is blocked by the marked step shape of the ice front, and that only the depth-varying (baroclinic) component, which is typically much smaller, can enter the sub-ice cavity. Our results arise from direct observations of the Getz Ice Shelf system and laboratory experiments on a rotating platform. A similar blocking of the barotropic component may occur in other areas with comparable ice-bathymetry configurations, which may explain why changes in the density structure of the water column have been found to be a better indicator of basal melt rate variability than the heat transported onto the continental shelf(9). Representing the step topography of the ice front accurately in models is thus important for simulating ocean heat fluxes and induced melt rates.


  
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.


  
Embryonal precursors of Wilms tumor 期刊论文
SCIENCE, 2019, 366 (6470) : 1247-+
作者:  Coorens, Tim H. H.;  Treger, Taryn D.;  Al-Saadi, Reem;  Moore, Luiza;  Tran, Maxine G. B.;  Mitchell, Thomas J.;  Tugnait, Suzanne;  Thevanesan, Christine;  Young, Matthew D.;  Oliver, Thomas R. W.;  Oostveen, Minou;  Collord, Grace;  Tarpey, Patrick S.;  Cagan, Alex;  Hooks, Yvette;  Brougham, Mark;  Reynolds, Ben C.;  Barone, Giuseppe;  Anderson, John;  Jorgensen, Mette;  Burke, G. A. Amos;  Visser, Johannes;  Nicholson, James C.;  Smeulders, Naima;  Mushtaq, Imran;  Stewart, Grant D.;  Campbell, Peter J.;  Wedge, David C.;  Martincorena, Inigo;  Rampling, Dyanne;  Hook, Liz;  Warren, Anne Y.;  Coleman, Nicholas;  Chowdhury, Tanzina;  Sebire, Neil;  Drost, Jarno;  Saeb-Parsy, Kourosh;  Stratton, Michael R.;  Straathof, Karin;  Pritchard-Jones, Kathy;  Behjati, Sam
收藏  |  浏览/下载:10/0  |  提交时间:2020/02/17
Recurrent intragenic rearrangements of EGFR and BRAF in soft tissue tumors of infants 期刊论文
NATURE COMMUNICATIONS, 2018, 9
作者:  Wegert, Jenny;  Vokuhl, Christian;  Collord, Grace;  Velasco-Herrera, Martin Del Castillo;  Farndon, Sarah J.;  Guzzo, Charlotte;  Jorgensen, Mette;  Anderson, John;  Slater, Olga;  Duncan, Catriona;  Bausenwein, Sabrina;  Streitenberger, Heike;  Ziegler, Barbara;  Furtwaengler, Rhoikos;  Graf, Norbert;  Stratton, Michael R.;  Campbell, Peter J.;  Jones, David T. W.;  Koelsche, Christian;  Pfister, Stefan M.;  Mifsud, William;  Sebire, Neil;  Sparber-Sauer, Monika;  Koscielniak, Ewa;  Rosenwald, Andreas;  Gessler, Manfred;  Behjati, Sam
收藏  |  浏览/下载:9/0  |  提交时间:2019/11/27
Partially methylated domains are hypervariable in breast cancer and fuel widespread CpG island hypermethylation 期刊论文
NATURE COMMUNICATIONS, 2019, 10
作者:  Brinkman, Arie B.;  Nik-Zainal, Serena;  Simmer, Femke;  Rodriguez-Gonzalez, F. German;  Smid, Marcel;  Alexandrov, Ludmil B.;  Butler, Adam;  Martink, Sancha;  Davies, Helen;  Glodzik, Dominik;  Zou, Xueqing;  Ramakrishna, Manasa;  Staaf, Johan;  Ringrier, Markus;  Sieuwerts, Anieta;  Ferrari, Anthony;  Morganella, Sandro;  Fleischer, Thomas;  Kristensen, Vessela;  Gut, Marta;  van de Vijver, Marc J.;  Borresen-Dale, Anne-Lise;  Richardson, Andrea L.;  Thomas, Gilles;  Gut, Ivo G.;  Martens, John W. M.;  Foekens, John A.;  Stratton, Michael R.;  Stunnenberg, Hendrik G.
收藏  |  浏览/下载:11/0  |  提交时间:2019/11/27
Somatic mutant clones colonize the human esophagus with age 期刊论文
SCIENCE, 2018, 362 (6417) : 911-+
作者:  Martincorena, Inigo;  Fowler, Joanna C.;  Wabik, Agnieszka;  Lawson, Andrew R. J.;  Abascal, Federico;  Hall, Michael W. J.;  Cagan, Alex;  Murai, Kasumi;  Mahbubani, Krishnaa;  Stratton, Michael R.;  Fitzgerald, Rebecca C.;  Handford, Penny A.;  Campbell, Peter J.;  Saeb-Parsy, Kourosh;  Jones, Philip H.
收藏  |  浏览/下载:11/0  |  提交时间:2019/11/27