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Structure of nevanimibe-bound tetrameric human ACAT1 期刊论文
NATURE, 2020, 581 (7808) : 339-U214
作者:  Ma, Xiyu;  Claus, Lucas A. N.;  Leslie, Michelle E.;  Tao, Kai;  Wu, Zhiping;  Liu, Jun;  Yu, Xiao;  Li, Bo;  Zhou, Jinggeng;  Savatin, Daniel V.;  Peng, Junmin;  Tyler, Brett M.;  Heese, Antje;  Russinova, Eugenia;  He, Ping;  Shan, Libo
收藏  |  浏览/下载:47/0  |  提交时间:2020/07/03

The structure of human ACAT1 in complex with the inhibitor nevanimibe is resolved by cryo-electron microscopy.


Cholesterol is an essential component of mammalian cell membranes, constituting up to 50% of plasma membrane lipids. By contrast, it accounts for only 5% of lipids in the endoplasmic reticulum (ER)(1). The ER enzyme sterol O-acyltransferase 1 (also named acyl-coenzyme A:cholesterol acyltransferase, ACAT1) transfers a long-chain fatty acid to cholesterol to form cholesteryl esters that coalesce into cytosolic lipid droplets. Under conditions of cholesterol overload, ACAT1 maintains the low cholesterol concentration of the ER and thereby has an essential role in cholesterol homeostasis(2,3). ACAT1 has also been implicated in Alzheimer'  s disease(4), atherosclerosis(5) and cancers(6). Here we report a cryo-electron microscopy structure of human ACAT1 in complex with nevanimibe(7), an inhibitor that is in clinical trials for the treatment of congenital adrenal hyperplasia. The ACAT1 holoenzyme is a tetramer that consists of two homodimers. Each monomer contains nine transmembrane helices (TMs), six of which (TM4-TM9) form a cavity that accommodates nevanimibe and an endogenous acyl-coenzyme A. This cavity also contains a histidine that has previously been identified as essential for catalytic activity(8). Our structural data and biochemical analyses provide a physical model to explain the process of cholesterol esterification, as well as details of the interaction between nevanimibe and ACAT1, which may help to accelerate the development of ACAT1 inhibitors to treat related diseases.


  
Paracrine orchestration of intestinal tumorigenesis by a mesenchymal niche 期刊论文
NATURE, 2020, 580 (7804) : 524-+
作者:  Poore, Gregory D.;  Kopylova, Evguenia;  Zhu, Qiyun;  Carpenter, Carolina;  Fraraccio, Serena;  Wandro, Stephen;  Kosciolek, Tomasz;  Janssen, Stefan;  Metcalf, Jessica;  Song, Se Jin;  Kanbar, Jad;  Miller-Montgomery, Sandrine;  Heaton, Robert;  Mckay, Rana;  Patel, Sandip Pravin;  Swafford, Austin D.;  Knight, Rob
收藏  |  浏览/下载:54/0  |  提交时间:2020/07/03

The initiation of an intestinal tumour is a probabilistic process that depends on the competition between mutant and normal epithelial stem cells in crypts(1). Intestinal stem cells are closely associated with a diverse but poorly characterized network of mesenchymal cell types(2,3). However, whether the physiological mesenchymal microenvironment of mutant stem cells affects tumour initiation remains unknown. Here we provide in vivo evidence that the mesenchymal niche controls tumour initiation in trans. By characterizing the heterogeneity of the intestinal mesenchyme using single-cell RNA-sequencing analysis, we identified a population of rare pericryptal Ptgs2-expressing fibroblasts that constitutively process arachidonic acid into highly labile prostaglandin E-2 (PGE(2)). Specific ablation of Ptgs2 in fibroblasts was sufficient to prevent tumour initiation in two different models of sporadic, autochthonous tumorigenesis. Mechanistically, single-cell RNA-sequencing analyses of a mesenchymal niche model showed that fibroblast-derived PGE(2) drives the expansion omicron f a population of Sca-1(+) reserve-like stem cells. These express a strong regenerative/tumorigenic program, driven by the Hippo pathway effector Yap. In vivo, Yap is indispensable for Sca-1(+) cell expansion and early tumour initiation and displays a nuclear localization in both mouse and human adenomas. Using organoid experiments, we identified a molecular mechanism whereby PGE(2) promotes Yap dephosphorylation, nuclear translocation and transcriptional activity by signalling through the receptor Ptger4. Epithelial-specific ablation of Ptger4 misdirected the regenerative reprogramming of stem cells and prevented Sca-1(+) cell expansion and sporadic tumour initiation in mutant mice, thereby demonstrating the robust paracrine control of tumour-initiating stem cells by PGE(2)-Ptger4. Analyses of patient-derived organoids established that PGE(2)-PTGER4 also regulates stem-cell function in humans. Our study demonstrates that initiation of colorectal cancer is orchestrated by the mesenchymal niche and reveals a mechanism by which rare pericryptal Ptgs2-expressing fibroblasts exert paracrine control over tumour-initiating stem cells via the druggable PGE(2)-Ptger4-Yap signalling axis.


Single-cell RNA-sequencing analysis of intestinal mesenchyme identified a population of fibroblasts that produce prostaglandin E-2, which, when disrupted, prevented initiation of intestinal tumours.


  
Constraint on the matter-antimatter symmetry-violating phase in neutrino oscillations 期刊论文
NATURE, 2020, 580 (7803) : 339-+
作者:  Houben, Lothar;  Weissman, Haim;  Wolf, Sharon G.;  Rybtchinski, Boris
收藏  |  浏览/下载:29/0  |  提交时间:2020/07/03

The charge-conjugation and parity-reversal (CP) symmetry of fundamental particles is a symmetry between matter and antimatter. Violation of this CP symmetry was first observed in 1964(1), and CP violation in the weak interactions of quarks was soon established(2). Sakharov proposed(3) that CP violation is necessary to explain the observed imbalance of matter and antimatter abundance in the Universe. However, CP violation in quarks is too small to support this explanation. So far, CP violation has not been observed in non-quark elementary particle systems. It has been shown that CP violation in leptons could generate the matter-antimatter disparity through a process called leptogenesis(4). Leptonic mixing, which appears in the standard model'  s charged current interactions(5,6), provides a potential source of CP violation through a complex phase dCP, which is required by some theoretical models of leptogenesis(7-9). This CP violation can be measured in muon neutrino to electron neutrino oscillations and the corresponding antineutrino oscillations, which are experimentally accessible using accelerator-produced beams as established by the Tokai-to-Kamioka (T2K) and NOvA experiments(10,11). Until now, the value of dCP has not been substantially constrained by neutrino oscillation experiments. Here we report a measurement using long-baseline neutrino and antineutrino oscillations observed by the T2K experiment that shows a large increase in the neutrino oscillation probability, excluding values of dCP that result in a large increase in the observed antineutrino oscillation probability at three standard deviations (3 sigma). The 3 sigma confidence interval for delta(CP), which is cyclic and repeats every 2p, is [-3.41, -0.03] for the so-called normal mass ordering and [-2.54, -0.32] for the inverted mass ordering. Our results indicate CP violation in leptons and our method enables sensitive searches for matter-antimatter asymmetry in neutrino oscillations using accelerator-produced neutrino beams. Future measurements with larger datasets will test whether leptonic CP violation is larger than the CP violation in quarks.


  
Loopy Levy flights enhance tracer diffusion in active suspensions 期刊论文
NATURE, 2020, 579 (7799) : 364-+
作者:  Hu, Bo;  Jin, Chengcheng;  Zeng, Xing;  Resch, Jon M.;  Jedrychowski, Mark P.;  Yang, Zongfang;  Desai, Bhavna N.;  Banks, Alexander S.;  Lowell, Bradford B.;  Mathis, Diane;  Spiegelman, Bruce M.
收藏  |  浏览/下载:24/0  |  提交时间:2020/07/03

A theoretical framework describing the hydrodynamic interactions between a passive particle and an active medium in out-of-equilibrium systems predicts long-range Levy flights for the diffusing particle driven by the density of the active component.


Brownian motion is widely used as a model of diffusion in equilibrium media throughout the physical, chemical and biological sciences. However, many real-world systems are intrinsically out of equilibrium owing to energy-dissipating active processes underlying their mechanical and dynamical features(1). The diffusion process followed by a passive tracer in prototypical active media, such as suspensions of active colloids or swimming microorganisms(2), differs considerably from Brownian motion, as revealed by a greatly enhanced diffusion coefficient(3-10) and non-Gaussian statistics of the tracer displacements(6,9,10). Although these characteristic features have been extensively observed experimentally, there is so far no comprehensive theory explaining how they emerge from the microscopic dynamics of the system. Here we develop a theoretical framework to model the hydrodynamic interactions between the tracer and the active swimmers, which shows that the tracer follows a non-Markovian coloured Poisson process that accounts for all empirical observations. The theory predicts a long-lived Levy flight regime(11) of the loopy tracer motion with a non-monotonic crossover between two different power-law exponents. The duration of this regime can be tuned by the swimmer density, suggesting that the optimal foraging strategy of swimming microorganisms might depend crucially on their density in order to exploit the Levy flights of nutrients(12). Our framework can be applied to address important theoretical questions, such as the thermodynamics of active systems(13), and practical ones, such as the interaction of swimming microorganisms with nutrients and other small particles(14) (for example, degraded plastic) and the design of artificial nanoscale machines(15).


  
Cell stress in cortical organoids impairs molecular subtype specification 期刊论文
NATURE, 2020, 578 (7793) : 142-+
作者:  Chen, Tao;  van Gelder, Jeroen;  van de Ven, Bram;  Amitonov, Sergey V.;  de Wilde, Bram;  Euler, Hans-Christian Ruiz;  Broersma, Hajo;  Bobbert, Peter A.;  Zwanenburg, Floris A.;  van der Wiel, Wilfred G.
收藏  |  浏览/下载:31/0  |  提交时间:2020/07/03

Cortical organoids are self-organizing three-dimensional cultures that model features of the developing human cerebral cortex(1,2). However, the fidelity of organoid models remains unclear(3-5). Here we analyse the transcriptomes of individual primary human cortical cells from different developmental periods and cortical areas. We find that cortical development is characterized by progenitor maturation trajectories, the emergence of diverse cell subtypes and areal specification of newborn neurons. By contrast, organoids contain broad cell classes, but do not recapitulate distinct cellular subtype identities and appropriate progenitor maturation. Although the molecular signatures of cortical areas emerge in organoid neurons, they are not spatially segregated. Organoids also ectopically activate cellular stress pathways, which impairs cell-type specification. However, organoid stress and subtype defects are alleviated by transplantation into the mouse cortex. Together, these datasets and analytical tools provide a framework for evaluating and improving the accuracy of cortical organoids as models of human brain development.


Single-cell RNA sequencing clarifies the development and specification of neurons in the human cortex and shows that cell stress impairs this process in cortical organoids.


  
Hidden diversity of vacancy networks in Prussian blue analogues 期刊论文
NATURE, 2020, 578 (7794) : 256-+
作者:  Hendrickx, N. W.;  Franke, D. P.;  Sammak, A.;  Scappucci, G.;  Veldhorst, M.
收藏  |  浏览/下载:25/0  |  提交时间:2020/07/03

Prussian blue analogues (PBAs) are a diverse family of microporous inorganic solids, known for their gas storage ability(1), metal-ion immobilization(2), proton conduction(3), and stimuli-dependent magnetic(4,5), electronic(6) and optical(7) properties. This family of materials includes the double-metal cyanide catalysts(8,9) and the hexacyanoferrate/ hexacyanomanganate battery materials(10,11). Central to the various physical properties of PBAs is their ability to reversibly transport mass, a process enabled by structural vacancies. Conventionally presumed to be random(12,13), vacancy arrangements are crucial because they control micropore-network characteristics, and hence the diffusivity and adsorption profiles(14,15). The long-standing obstacle to characterizing the vacancy networks of PBAs is the inaccessibility of single crystals(16). Here we report the growth of single crystals of various PBAs and the measurement and interpretation of their X-ray diffuse scattering patterns. We identify a diversity of non-random vacancy arrangements that is hidden from conventional crystallographic powder analysis. Moreover, we explain this unexpected phase complexity in terms of a simple microscopic model that is based on local rules of electroneutrality and centrosymmetry. The hidden phase boundaries that emerge demarcate vacancynetwork polymorphs with very different micropore characteristics. Our results establish a foundation for correlated defect engineering in PBAs as a means of controlling storage capacity, anisotropy and transport efficiency.


  
The emergence of transcriptional identity in somatosensory neurons 期刊论文
NATURE, 2020, 577 (7790) : 392-+
作者:  Sharma, Nikhil;  Flaherty, Kali;  Lezgiyeva, Karina;  Wagner, Daniel E.;  Klein, Allon M.;  Ginty, David D.
收藏  |  浏览/下载:18/0  |  提交时间:2020/07/03

More than twelve morphologically and physiologically distinct subtypes of primary somatosensory neuron report salient features of our internal and external environments(1-4). It is unclear how specialized gene expression programs emerge during development to endow these subtypes with their unique properties. To assess the developmental progression of transcriptional maturation of each subtype of principal somatosensory neuron, we generated a transcriptomic atlas of cells traversing the primary somatosensory neuron lineage in mice. Here we show that somatosensory neurogenesis gives rise to neurons in a transcriptionally unspecialized state, characterized by co-expression of transcription factors that become restricted to select subtypes as development proceeds. Single-cell transcriptomic analyses of sensory neurons from mutant mice lacking transcription factors suggest that these broad-to-restricted transcription factors coordinate subtype-specific gene expression programs in subtypes in which their expression is maintained. We also show that neuronal targets are involved in this process  disruption of the prototypic target-derived neurotrophic factor NGF leads to aberrant subtype-restricted patterns of transcription factor expression. Our findings support a model in which cues that emanate from intermediate and final target fields promote neuronal diversification in part by transitioning cells from a transcriptionally unspecialized state to transcriptionally distinct subtypes by modulating the selection of subtype-restricted transcription factors.


  
Downscaling climate change of mean climatology and extremes of precipitation and temperature: Application to a Mediterranean climate basin 期刊论文
INTERNATIONAL JOURNAL OF CLIMATOLOGY, 2019, 39 (13) : 4985-5005
作者:  Zhang, Rong;  Corte-Real, Joao;  Moreira, Madalena;  Kilsby, Chris;  Burton, Aidan;  Fowler, Hayley J.;  Blenkinsop, Stephen;  Birkinshaw, Stephen;  Forsythe, Nathan;  Nunes, Joao P.;  Sampaio, Elsa
收藏  |  浏览/下载:25/0  |  提交时间:2020/02/17
dry spell  heat wave  hydrological impact assessment  Mediterranean climate  precipitation model  second-order autoregressive process  weather generator  
Modelling of energy consumption and carbon emission from the building construction sector in China, a process-based LCA approach 期刊论文
ENERGY POLICY, 2019, 134
作者:  Zhang, Yang;  Yan, Da;  Hu, Shan;  Guo, Siyue
收藏  |  浏览/下载:18/0  |  提交时间:2020/02/17
Embodied energy  Carbon emissions  Building construction  Process-based LCA model  
Forecasting species range dynamics with process-explicit models: matching methods to applications 期刊论文
ECOLOGY LETTERS, 2019, 22 (11) : 1940-1956
作者:  Briscoe, Natalie J.;  Elith, Jane;  Salguero-Gomez, Roberto;  Lahoz-Monfort, Jose J.;  Camac, James S.;  Giljohann, Katherine M.;  Holden, Matthew H.;  Hradsky, Bronwyn A.;  Kearney, Michael R.;  McMahon, Sean M.;  Phillips, Ben L.;  Regan, Tracey J.;  Rhodes, Jonathan R.;  Vesk, Peter A.;  Wintle, Brendan A.;  Yen, Jian D. L.;  Guillera-Arroita, Gurutzeta
收藏  |  浏览/下载:23/0  |  提交时间:2019/11/27
Demography  mechanistic  population dynamics  process-based models  species distribution model