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A developmental landscape of 3D-cultured human pre-gastrulation embryos 期刊论文
NATURE, 2020, 577 (7791) : 537-+
作者:  Xiang, Lifeng;  Yin, Yu;  Zheng, Yun;  Ma, Yanping;  Li, Yonggang;  Zhao, Zhigang;  Guo, Junqiang;  Ai, Zongyong;  Niu, Yuyu;  Duan, Kui;  He, Jingjing;  Ren, Shuchao;  Wu, Dan;  Bai, Yun;  Shang, Zhouchun;  Dai, Xi;  Ji, Weizhi;  Li, Tianqing
收藏  |  浏览/下载:12/0  |  提交时间:2020/07/03

Our understanding of how human embryos develop before gastrulation, including spatial self-organization and cell type ontogeny, remains limited by available two-dimensional technological platforms(1,2) that do not recapitulate the in vivo conditions(3-5). Here we report a three-dimensional (3D) blastocyst-culture system that enables human blastocyst development up to the primitive streak anlage stage. These 3D embryos mimic developmental landmarks and 3D architectures in vivo, including the embryonic disc, amnion, basement membrane, primary and primate unique secondary yolk sac, formation of anterior-posterior polarity and primitive streak anlage. Using single-cell transcriptome profiling, we delineate ontology and regulatory networks that underlie the segregation of epiblast, primitive endoderm and trophoblast. Compared with epiblasts, the amniotic epithelium shows unique and characteristic phenotypes. After implantation, specific pathways and transcription factors trigger the differentiation of cytotrophoblasts, extravillous cytotrophoblasts and syncytiotrophoblasts. Epiblasts undergo a transition to pluripotency upon implantation, and the transcriptome of these cells is maintained until the generation of the primitive streak anlage. These developmental processes are driven by different pluripotency factors. Together, findings from our 3D-culture approach help to determine the molecular and morphogenetic developmental landscape that occurs during human embryogenesis.


A 3D culture system to model human embryonic development, together with single-cell transcriptome profiling, provides insights into the molecular developmental landscape during human post-implantation embryogenesis.


  
Cortical pattern generation during dexterous movement is input-driven 期刊论文
NATURE, 2020, 577 (7790) : 386-+
作者:  Cyranoski, David
收藏  |  浏览/下载:9/0  |  提交时间:2020/07/03

The motor cortex controls skilled arm movement by sending temporal patterns of activity to lower motor centres(1). Local cortical dynamics are thought to shape these patterns throughout movement execution(2-4). External inputs have been implicated in setting the initial state of the motor cortex(5,6), but they may also have a pattern-generating role. Here we dissect the contribution of local dynamics and inputs to cortical pattern generation during a prehension task in mice. Perturbing cortex to an aberrant state prevented movement initiation, but after the perturbation was released, cortex either bypassed the normal initial state and immediately generated the pattern that controls reaching or failed to generate this pattern. The difference in these two outcomes was probably a result of external inputs. We directly investigated the role of inputs by inactivating the thalamus  this perturbed cortical activity and disrupted limb kinematics at any stage of the movement. Activation of thalamocortical axon terminals at different frequencies disrupted cortical activity and arm movement in a graded manner. Simultaneous recordings revealed that both thalamic activity and the current state of cortex predicted changes in cortical activity. Thus, the pattern generator for dexterous arm movement is distributed across multiple, strongly interacting brain regions.


  
Turning connective tissue into neurons for 10 years 期刊论文
NATURE, 2020, 578 (7796) : 522-524
作者:  Acquaviva, Laurent;  Boekhout, Michiel;  Karasu, Mehmet E.;  Brick, Kevin;  Pratto, Florencia;  Li, Tao;  van Overbeek, Megan;  Kauppi, Liisa;  Camerini-Otero, R. Daniel;  Jasin, Maria;  Keeney, Scott
收藏  |  浏览/下载:11/0  |  提交时间:2020/07/03

An historic breakthrough that altered our understanding of cell fate.


A method for directly converting connective-tissue cells into neurons opened up a new branch of research into cell-based therapies and called into question long-held beliefs about how development affects a cell'  s identity.


  
Molecular tuning of CO2-to-ethylene conversion 期刊论文
NATURE, 2020, 577 (7791) : 509-+
作者:  Li, Fengwang;  39;Brien, Colin P.
收藏  |  浏览/下载:11/0  |  提交时间:2020/07/03

The electrocatalytic reduction of carbon dioxide, powered by renewable electricity, to produce valuable fuels and feedstocks provides a sustainable and carbon-neutral approach to the storage of energy produced by intermittent renewable sources(1). However, the highly selective generation of economically desirable products such as ethylene from the carbon dioxide reduction reaction (CO2RR) remains a challenge(2). Tuning the stabilities of intermediates to favour a desired reaction pathway can improve selectivity(3-5), and this has recently been explored for the reaction on copper by controlling morphology(6), grain boundaries(7), facets(8), oxidation state(9) and dopants(10). Unfortunately, the Faradaic efficiency for ethylene is still low in neutral media (60 per cent at a partial current density of 7 milliamperes per square centimetre in the best catalyst reported so far(9)), resulting in a low energy efficiency. Here we present a molecular tuning strategy-the functionalization of the surface of electrocatalysts with organic molecules-that stabilizes intermediates for more selective CO2RR to ethylene. Using electrochemical, operando/in situ spectroscopic and computational studies, we investigate the influence of a library of molecules, derived by electro-dimerization of arylpyridiniums(11), adsorbed on copper. We find that the adhered molecules improve the stabilization of an '  atop-bound'  CO intermediate (that is, an intermediate bound to a single copper atom), thereby favouring further reduction to ethylene. As a result of this strategy, we report the CO2RR to ethylene with a Faradaic efficiency of 72 per cent at a partial current density of 230 milliamperes per square centimetre in a liquid-electrolyte flow cell in a neutral medium. We report stable ethylene electrosynthesis for 190 hours in a system based on a membrane-electrode assembly that provides a full-cell energy efficiency of 20 per cent. We anticipate that this may be generalized to enable molecular strategies to complement heterogeneous catalysts by stabilizing intermediates through local molecular tuning.


Electrocatalytic reduction of CO2 over copper can be made highly selective by '  tuning'  the copper surface with adsorbed organic molecules to stabilize intermediates for carbon-based fuels such as ethylene


  
Hidden neural states underlie canary song syntax 期刊论文
NATURE, 2020
作者:  Bao, Han;  Duan, Junlei;  Jin, Shenchao;  Lu, Xingda;  Li, Pengxiong;  Qu, Weizhi;  Wang, Mingfeng;  Novikova, Irina;  Mikhailov, Eugeniy E.;  Zhao, Kai-Feng;  Molmer, Klaus;  Shen, Heng;  Xiao, Yanhong
收藏  |  浏览/下载:10/0  |  提交时间:2020/07/03

Neurons in the canary premotor cortex homologue encode past song phrases and transitions, carrying information relevant to future choice of phrases as '  hidden states'  during song.


Coordinated skills such as speech or dance involve sequences of actions that follow syntactic rules in which transitions between elements depend on the identities and order of past actions. Canary songs consist of repeated syllables called phrases, and the ordering of these phrases follows long-range rules(1)in which the choice of what to sing depends on the song structure many seconds prior. The neural substrates that support these long-range correlations are unknown. Here, using miniature head-mounted microscopes and cell-type-specific genetic tools, we observed neural activity in the premotor nucleus HVC(2-4)as canaries explored various phrase sequences in their repertoire. We identified neurons that encode past transitions, extending over four phrases and spanning up to four seconds and forty syllables. These neurons preferentially encode past actions rather than future actions, can reflect more than one song history, and are active mostly during the rare phrases that involve history-dependent transitions in song. These findings demonstrate that the dynamics of HVC include '  hidden states'  that are not reflected in ongoing behaviour but rather carry information about prior actions. These states provide a possible substrate for the control of syntax transitions governed by long-range rules.


  
Months-long thousand-kilometre-scale wobbling before great subduction earthquakes 期刊论文
NATURE, 2020, 580 (7805) : 628-+
作者:  Son, Hyungmok;  Park, Juliana J.;  Ketterle, Wolfgang;  Jamison, Alan O.
收藏  |  浏览/下载:16/0  |  提交时间:2020/05/13

Observed reversals in GNSS surface motions suggests greatly enhanced slab pull in the months preceding the great subduction earthquakes in Maule (Chile, 2010) and Tohoku-oki (Japan, 2011) of moment magnitudes 8.8 and 9.0.


Megathrust earthquakes are responsible for some of the most devastating natural disasters(1). To better understand the physical mechanisms of earthquake generation, subduction zones worldwide are continuously monitored with geophysical instrumentation. One key strategy is to install stations that record signals from Global Navigation Satellite Systems(2,3) (GNSS), enabling us to track the non-steady surface motion of the subducting and overriding plates before, during and after the largest events(4-6). Here we use a recently developed trajectory modelling approach(7) that is designed to isolate secular tectonic motions from the daily GNSS time series to show that the 2010 Maule, Chile (moment magnitude 8.8) and 2011 Tohoku-oki, Japan (moment magnitude 9.0) earthquakes were preceded by reversals of 4-8 millimetres in surface displacement that lasted several months and spanned thousands of kilometres. Modelling of the surface displacement reversal that occurred before the Tohoku-oki earthquake suggests an initial slow slip followed by a sudden pulldown of the Philippine Sea slab so rapid that it caused a viscoelastic rebound across the whole of Japan. Therefore, to understand better when large earthquakes are imminent, we must consider not only the evolution of plate interface frictional processes but also the dynamic boundary conditions from deeper subduction processes, such as sudden densification of metastable slab.


  
Iron-based binary ferromagnets for transverse thermoelectric conversion 期刊论文
NATURE, 2020, 581 (7806) : 53-+
作者:  Grun, Rainer;  Pike, Alistair;  McDermott, Frank;  Eggins, Stephen;  Mortimer, Graham;  Aubert, Maxime;  Kinsley, Lesley;  Joannes-Boyau, Renaud;  Rumsey, Michael;  Denys, Christiane;  Brink, James;  Clark, Tara;  Stringer, Chris
收藏  |  浏览/下载:31/0  |  提交时间:2020/07/03

Aluminium- and gallium-doped iron compounds show a large anomalous Nernst effect owing to a topological electronic structure, and their films are potentially suitable for designing low-cost, flexible microelectronic thermoelectric generators.


Thermoelectric generation using the anomalous Nernst effect (ANE) has great potential for application in energy harvesting technology because the transverse geometry of the Nernst effect should enable efficient, large-area and flexible coverage of a heat source. For such applications to be viable, substantial improvements will be necessary not only for their performance but also for the associated material costs, safety and stability. In terms of the electronic structure, the anomalous Nernst effect (ANE) originates from the Berry curvature of the conduction electrons near the Fermi energy(1,2). To design a large Berry curvature, several approaches have been considered using nodal points and lines in momentum space(3-10). Here we perform a high-throughput computational search and find that 25 percent doping of aluminium and gallium in alpha iron, a naturally abundant and low-cost element, dramatically enhances the ANE by a factor of more than ten, reaching about 4 and 6 microvolts per kelvin at room temperature, respectively, close to the highest value reported so far. The comparison between experiment and theory indicates that the Fermi energy tuning to the nodal web-a flat band structure made of interconnected nodal lines-is the key for the strong enhancement in the transverse thermoelectric coefficient, reaching a value of about 5 amperes per kelvin per metre with a logarithmic temperature dependence. We have also succeeded in fabricating thin films that exhibit a large ANE at zero field, which could be suitable for designing low-cost, flexible microelectronic thermoelectric generators(11-13).


  
Quantum entanglement between an atom and a molecule 期刊论文
NATURE, 2020, 581 (7808) : 273-+
作者:  Trisos, Christopher H.;  Merow, Cory;  Pigot, Alex L.
收藏  |  浏览/下载:30/0  |  提交时间:2020/07/03

Conventional information processors convert information between different physical carriers for processing, storage and transmission. It seems plausible that quantum information will also be held by different physical carriers in applications such as tests of fundamental physics, quantum enhanced sensors and quantum information processing. Quantum controlled molecules, in particular, could transduce quantum information across a wide range of quantum bit (qubit) frequencies-from a few kilohertz for transitions within the same rotational manifold(1), a few gigahertz for hyperfine transitions, a few terahertz for rotational transitions, to hundreds of terahertz for fundamental and overtone vibrational and electronic transitions-possibly all within the same molecule. Here we demonstrate entanglement between the rotational states of a (CaH+)-Ca-40 molecular ion and the internal states of a Ca-40(+) atomic ion(2). We extend methods used in quantum logic spectroscopy(1,3) for pure-state initialization, laser manipulation and state readout of the molecular ion. The quantum coherence of the Coulomb coupled motion between the atomic and molecular ions enables subsequent entangling manipulations. The qubit addressed in the molecule has a frequency of either 13.4 kilohertz(1) or 855 gigahertz(3), highlighting the versatility of molecular qubits. Our work demonstrates how molecules can transduce quantum information between qubits with different frequencies to enable hybrid quantum systems. We anticipate that our method of quantum control and measurement of molecules will find applications in quantum information science, quantum sensors, fundamental and applied physics, and controlled quantum chemistry.


Quantum entanglement is realized between rotational levels of a molecular ion with energy differences spanning several orders of magnitude and long-lived internal states of a single atomic ion.


  
CRISPR screen in regulatory T cells reveals modulators of Foxp3 期刊论文
NATURE, 2020
作者:  Xu, Daqian;  Wang, Zheng;  Xia, Yan;  Shao, Fei;  Xia, Weiya;  Wei, Yongkun;  Li, Xinjian;  Qian, Xu;  Lee, Jong-Ho;  Du, Linyong;  Zheng, Yanhua;  Lv, Guishuai;  Leu, Jia-shiun;  Wang, Hongyang;  Xing, Dongming;  Liang, Tingbo;  Hung, Mien-Chie;  Lu, Zhimin
收藏  |  浏览/下载:33/0  |  提交时间:2020/07/03

Regulatory T (T-reg) cells are required to control immune responses and maintain homeostasis, but are a significant barrier to antitumour immunity(1). Conversely, T-reg instability, characterized by loss of the master transcription factor Foxp3 and acquisition of proinflammatory properties(2), can promote autoimmunity and/or facilitate more effective tumour immunity(3,4). A comprehensive understanding of the pathways that regulate Foxp3 could lead to more effective T-reg therapies for autoimmune disease and cancer. The availability of new functional genetic tools has enabled the possibility of systematic dissection of the gene regulatory programs that modulate Foxp3 expression. Here we developed a CRISPR-based pooled screening platform for phenotypes in primary mouse T-reg cells and applied this technology to perform a targeted loss-of-function screen of around 500 nuclear factors to identify gene regulatory programs that promote or disrupt Foxp3 expression. We identified several modulators of Foxp3 expression, including ubiquitin-specific peptidase 22 (Usp22) and ring finger protein 20 (Rnf20). Usp22, a member of the deubiquitination module of the SAGA chromatin-modifying complex, was revealed to be a positive regulator that stabilized Foxp3 expression  whereas the screen suggested that Rnf20, an E3 ubiquitin ligase, can serve as a negative regulator of Foxp3. T-reg-specific ablation of Usp22 in mice reduced Foxp3 protein levels and caused defects in their suppressive function that led to spontaneous autoimmunity but protected against tumour growth in multiple cancer models. Foxp3 destabilization in Usp22-deficient T-reg cells could be rescued by ablation of Rnf20, revealing a reciprocal ubiquitin switch in T-reg cells. These results reveal previously unknown modulators of Foxp3 and demonstrate a screening method that can be broadly applied to discover new targets for T-reg immunotherapies for cancer and autoimmune disease.


A CRISPR-based screening platform was used to identify previously uncharacterized genes that regulate the regulatory T cell-specific master transcription factor Foxp3, indicating that this screening method may be broadly applicable for the discovery of other genes involved in autoimmunity and immune responses to cancer.


  
Pharmacologic fibroblast reprogramming into photoreceptors restores vision 期刊论文
NATURE, 2020, 581 (7806) : 83-+
作者:  Jiang, Mingkai;  Medlyn, Belinda E.;  Drake, John E.;  Duursma, Remko A.;  Anderson, Ian C.;  Barton, Craig V. M.;  Boer, Matthias M.;  Carrillo, Yolima;  Castaneda-Gomez, Laura;  Collins, Luke;  Crous, Kristine Y.;  De Kauwe, Martin G.;  dos Santos, Bruna M.;  Emmerson, Kathryn M.;  Facey, Sarah L.;  Gherlenda, Andrew N.;  Gimeno, Teresa E.;  Hasegawa, Shun;  Johnson, Scott N.;  Kannaste, Astrid;  Macdonald, Catriona A.;  Mahmud, Kashif;  Moore, Ben D.;  Nazaries, Loic;  Neilson, Elizabeth H. J.;  Nielsen, Uffe N.;  Niinemets, Ulo;  Noh, Nam Jin;  Ochoa-Hueso, Raul;  Pathare, Varsha S.;  Pendall, Elise;  Pihlblad, Johanna;  Pineiro, Juan;  Powell, Jeff R.;  Power, Sally A.;  Reich, Peter B.;  Renchon, Alexandre A.;  Riegler, Markus;  Rinnan, Riikka;  Rymer, Paul D.;  Salomon, Roberto L.;  Singh, Brajesh K.;  Smith, Benjamin;  Tjoelker, Mark G.;  Walker, Jennifer K. M.;  Wujeska-Klause, Agnieszka;  Yang, Jinyan;  Zaehle, Soenke;  Ellsworth, David S.
收藏  |  浏览/下载:46/0  |  提交时间:2020/07/03

Photoreceptor loss is the final common endpoint in most retinopathies that lead to irreversible blindness, and there are no effective treatments to restore vision(1,2). Chemical reprogramming of fibroblasts offers an opportunity to reverse vision loss  however, the generation of sensory neuronal subtypes such as photoreceptors remains a challenge. Here we report that the administration of a set of five small molecules can chemically induce the transformation of fibroblasts into rod photoreceptor-like cells. The transplantation of these chemically induced photoreceptor-like cells (CiPCs) into the subretinal space of rod degeneration mice (homozygous for rd1, also known as Pde6b) leads to partial restoration of the pupil reflex and visual function. We show that mitonuclear communication is a key determining factor for the reprogramming of fibroblasts into CiPCs. Specifically, treatment with these five compounds leads to the translocation of AXIN2 to the mitochondria, which results in the production of reactive oxygen species, the activation of NF-kappa B and the upregulation of Ascl1. We anticipate that CiPCs could have therapeutic potential for restoring vision.


A set of five small molecules can induce the transformation of fibroblasts into rod photoreceptor-like cells, which can partially restore pupil reflex and visual function when transplanted into a rod degeneration mouse model.