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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:19/0  |  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.


  
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.


  
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