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In vivo imaging of mitochondrial membrane potential in non-small-cell lung cancer (vol 575, pg 380, 2019) 期刊论文
NATURE, 2020, 577 (7791) : E7-E7
作者:  Momcilovic, Milica;  Jones, Anthony;  Bailey, Sean T.;  Waldmann, Christopher M.;  Li, Rui;  Lee, Jason T.;  Abdelhady, Gihad;  Gomez, Adrian;  Holloway, Travis;  Schmid, Ernst;  Stout, David;  Fishbein, Michael C.;  Stiles, Linsey;  Dabir, Deepa V.;  Dubinett, Steven M.;  Christofk, Heather;  Shirihai, Orian;  Koehler, Carla M.;  Sadeghi, Saman;  Shackelford, David B.
收藏  |  浏览/下载:13/0  |  提交时间:2020/07/03
Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer's disease 期刊论文
NATURE, 2020, 577 (7790) : 399-+
作者:  Gate, David;  Saligrama, Naresha;  Leventhal, Olivia;  Yang, Andrew C.;  Unger, Michael S.;  Middeldorp, Jinte;  Chen, Kelly;  Lehallier, Benoit;  Channappa, Divya;  De Los Santos, Mark B.;  McBride, Alisha;  Pluvinage, John;  Elahi, Fanny;  Tam, Grace Kyin-Ye;  Kim, Yongha;  Greicius, Michael;  Wagner, Anthony D.;  Aigner, Ludwig;  Galasko, Douglas R.;  Davis, Mark M.;  Wyss-Coray, Tony
收藏  |  浏览/下载:6/0  |  提交时间:2020/07/03

Alzheimer'  s disease is an incurable neurodegenerative disorder in which neuroinflammation has a critical function(1). However, little is known about the contribution of the adaptive immune response in Alzheimer'  s disease(2). Here, using integrated analyses of multiple cohorts, we identify peripheral and central adaptive immune changes in Alzheimer'  s disease. First, we performed mass cytometry of peripheral blood mononuclear cells and discovered an immune signature of Alzheimer'  s disease that consists of increased numbers of CD8(+) T effector memory CD45RA(+) (T-EMRA) cells. In a second cohort, we found that CD8(+) T-EMRA cells were negatively associated with cognition. Furthermore, single-cell RNA sequencing revealed that T cell receptor (TCR) signalling was enhanced in these cells. Notably, by using several strategies of single-cell TCR sequencing in a third cohort, we discovered clonally expanded CD8(+) T-EMRA cells in the cerebrospinal fluid of patients with Alzheimer'  s disease. Finally, we used machine learning, cloning and peptide screens to demonstrate the specificity of clonally expanded TCRs in the cerebrospinal fluid of patients with Alzheimer'  s disease to two separate Epstein-Barr virus antigens. These results reveal an adaptive immune response in the blood and cerebrospinal fluid in Alzheimer'  s disease and provide evidence of clonal, antigen-experienced T cells patrolling the intrathecal space of brains affected by age-related neurodegeneration.


  
WHAT SCIENTISTS WANT TO KNOW ABOUT THE CORONAVIRUS OUTBREAK 期刊论文
NATURE, 2020, 577 (7792) : 605-607
作者:  Shade, Kai-Ting C.;  Conroy, Michelle E.;  Washburn, Nathaniel;  Kitaoka, Maya;  Huynh, Daniel J.;  Laprise, Emma;  Patil, Sarita U.;  Shreffler, Wayne G.;  Anthony, Robert M.
收藏  |  浏览/下载:17/0  |  提交时间:2020/07/03
Mutations that prevent caspase cleavage of RIPK1 cause autoinflammatory disease 期刊论文
NATURE, 2020, 577 (7788) : 103-+
作者:  Lalaoui, Najoua;  Boyden, Steven E.;  Oda, Hirotsugu;  Wood, Geryl M.;  Stone, Deborah L.;  Chau, Diep;  Liu, Lin;  Stoffels, Monique;  Kratina, Tobias;  Lawlor, Kate E.;  Zaal, Kristien J. M.;  Hoffmann, Patrycja M.;  Etemadi, Nima;  Shield-Artin, Kristy;  Biben, Christine;  Tsai, Wanxia Li;  Blake, Mary D.;  Kuehn, Hye Sun;  Yang, Dan;  Anderton, Holly;  Silke, Natasha;  Wachsmuth, Laurens;  Zheng, Lixin;  Moura, Natalia Sampaio;  Beck, David B.;  Gutierrez-Cruz, Gustavo;  Ombrello, Amanda K.;  Pinto-Patarroyo, Gineth P.;  Kueh, Andrew J.;  Herold, Marco J.;  Hall, Cathrine;  Wang, Hongying;  Chae, Jae Jin;  Dmitrieva, Natalia I.;  McKenzie, Mark;  Light, Amanda;  Barham, Beverly K.;  Jones, Anne;  Romeo, Tina M.;  Zhou, Qing;  Aksentijevich, Ivona;  Mullikin, James C.;  Gross, Andrew J.;  Shum, Anthony K.;  Hawkins, Edwin D.;  Masters, Seth L.;  Lenardo, Michael J.;  Boehm, Manfred;  Rosenzweig, Sergio D.;  Pasparakis, Manolis;  Voss, Anne K.;  Gadina, Massimo;  Kastner, Daniel L.;  Silke, John
收藏  |  浏览/下载:24/0  |  提交时间:2020/07/03

RIPK1 is a key regulator of innate immune signalling pathways. To ensure an optimal inflammatory response, RIPK1 is regulated post-translationally by well-characterized ubiquitylation and phosphorylation events, as well as by caspase-8-mediated cleavage1-7. The physiological relevance of this cleavage event remains unclear, although it is thought to inhibit activation of RIPK3 and necroptosis8. Here we show that the heterozygous missense mutations D324N, D324H and D324Y prevent caspase cleavage of RIPK1 in humans and result in an early-onset periodic fever syndrome and severe intermittent lymphadenopathy-a condition we term '  cleavage-resistant RIPK1-induced autoinflammatory syndrome'  . To define the mechanism for this disease, we generated a cleavage-resistant Ripk1(D325A) mutant mouse strain. Whereas Ripk1(-/-) mice died postnatally from systemic inflammation, Ripk1(D325A/D325A) mice died during embryogenesis. Embryonic lethality was completely prevented by the combined loss of Casp8 and Ripk3, but not by loss of Ripk3 or Mlkl alone. Loss of RIPK1 kinase activity also prevented Ripk1(D325A/D325A) embryonic lethality, although the mice died before weaning from multi-organ inflammation in a RIPK3-dependent manner. Consistently, Ripk1(D325A/D325A) and Ripk1(D325A/+) cells were hypersensitive to RIPK3-dependent TNF-induced apoptosis and necroptosis. Heterozygous Ripk1(D325A/+) mice were viable and grossly normal, but were hyper-responsive to inflammatory stimuli in vivo. Our results demonstrate the importance of caspase-mediated RIPK1 cleavage during embryonic development and show that caspase cleavage of RIPK1 not only inhibits necroptosis but also maintains inflammatory homeostasis throughout life.


  
Observation of Bose-Einstein condensates in an Earth-orbiting research lab 期刊论文
NATURE, 2020, 582 (7811) : 103-+
作者:  Yamamoto, Keisuke;  Venida, Anthony;  Yano, Julian;  Biancur, Douglas E.;  Kakiuchi, Miwako;  Gupta, Suprit;  Sohn, Albert S. W.;  Mukhopadhyay, Subhadip;  Lin, Elaine Y.;  Parker, Seth J.;  Banh, Robert S.;  Paulo, Joao A.;  Wen, Kwun Wah;  Debnath, Jayanta;  Kim, Grace E.;  Mancias, Joseph D.;  Fearon, Douglas T.;  Perera, Rushika M.;  Kimmelman, Alec C.
收藏  |  浏览/下载:25/0  |  提交时间:2020/07/03

Quantum mechanics governs the microscopic world, where low mass and momentum reveal a natural wave-particle duality. Magnifying quantum behaviour to macroscopic scales is a major strength of the technique of cooling and trapping atomic gases, in which low momentum is engineered through extremely low temperatures. Advances in this field have achieved such precise control over atomic systems that gravity, often negligible when considering individual atoms, has emerged as a substantial obstacle. In particular, although weaker trapping fields would allow access to lower temperatures(1,2), gravity empties atom traps that are too weak. Additionally, inertial sensors based on cold atoms could reach better sensitivities if the free-fall time of the atoms after release from the trap could be made longer(3). Planetary orbit, specifically the condition of perpetual free-fall, offers to lift cold-atom studies beyond such terrestrial limitations. Here we report production of rubidium Bose-Einstein condensates (BECs) in an Earth-orbiting research laboratory, the Cold Atom Lab. We observe subnanokelvin BECs in weak trapping potentials with free-expansion times extending beyond one second, providing an initial demonstration of the advantages offered by a microgravity environment for cold-atom experiments and verifying the successful operation of this facility. With routine BEC production, continuing operations will support long-term investigations of trap topologies unique to microgravity(4,5), atom-laser sources(6), few-body physics(7,8)and pathfinding techniques for atom-wave interferometry(9-12).


  
Simulation of Hubbard model physics in WSe2/WS2 moire superlattices 期刊论文
NATURE, 2020, 579 (7799) : 353-+
作者:  Stein, Reed M.;  Kang, Hye Jin;  McCorvy, John D.;  Glatfelter, Grant C.;  Jones, Anthony J.;  Che, Tao;  Slocum, Samuel;  Huang, Xi-Ping;  Savych, Olena;  Moroz, Yurii S.;  Stauch, Benjamin;  Johansson, Linda C.;  Cherezov, Vadim;  Kenakin, Terry;  Irwin, John J.;  Shoichet, Brian K.;  Roth, Bryan L.;  Dubocovich, Margarita L.
收藏  |  浏览/下载:8/0  |  提交时间:2020/07/03

Study of WSe2/WS2 moire superlattices reveals the phase diagram of the triangular-lattice Hubbard model, including a Mott insulating state at half-filling and a possible magnetic quantum phase transition near 0.6 filling.


The Hubbard model, formulated by physicist John Hubbard in the 1960s(1), is a simple theoretical model of interacting quantum particles in a lattice. The model is thought to capture the essential physics of high-temperature superconductors, magnetic insulators and other complex quantum many-body ground states(2,3). Although the Hubbard model provides a greatly simplified representation of most real materials, it is nevertheless difficult to solve accurately except in the one-dimensional case(2,3). Therefore, the physical realization of the Hubbard model in two or three dimensions, which can act as an analogue quantum simulator (that is, it can mimic the model and simulate its phase diagram and dynamics(4,5)), has a vital role in solving the strong-correlation puzzle, namely, revealing the physics of a large number of strongly interacting quantum particles. Here we obtain the phase diagram of the two-dimensional triangular-lattice Hubbard model by studying angle-aligned WSe2/WS2 bilayers, which form moire superlattices(6) because of the difference between the lattice constants of the two materials. We probe the charge and magnetic properties of the system by measuring the dependence of its optical response on an out-of-plane magnetic field and on the gate-tuned carrier density. At half-filling of the first hole moire superlattice band, we observe a Mott insulating state with antiferromagnetic Curie-Weiss behaviour, as expected for a Hubbard model in the strong-interaction regime(2,3,7-9). Above half-filling, our experiment suggests a possible quantum phase transition from an antiferromagnetic to a weak ferromagnetic state at filling factors near 0.6. Our results establish a new solid-state platform based on moire superlattices that can be used to simulate problems in strong-correlation physics that are described by triangular-lattice Hubbard models.


  
Premature mortality related to United States cross-state air pollution 期刊论文
NATURE, 2020, 578 (7794) : 261-+
作者:  Helmink, Beth A.;  Reddy, Sangeetha M.;  Gao, Jianjun;  Zhang, Shaojun;  Basar, Rafet;  Thakur, Rohit;  Yizhak, Keren;  Sade-Feldman, Moshe;  Blando, Jorge;  Han, Guangchun;  Gopalakrishnan, Vancheswaran;  Xi, Yuanxin;  Zhao, Hao;  Amaria, Rodabe N.;  Tawbi, Hussein A.;  Cogdill, Alex P.;  Liu, Wenbin;  LeBleu, Valerie S.;  Kugeratski, Fernanda G.;  Patel, Sapna;  Davies, Michael A.;  Hwu, Patrick;  Lee, Jeffrey E.;  Gershenwald, Jeffrey E.;  Lucci, Anthony;  Arora, Reetakshi;  Woodman, Scott;  Keung, Emily Z.;  Gaudreau, Pierre-Olivier;  Reuben, Alexandre;  Spencer, Christine N.;  Burton, Elizabeth M.;  Haydu, Lauren E.;  Lazar, Alexander J.;  Zapassodi, Roberta;  Hudgens, Courtney W.;  Ledesma, Deborah A.;  Ong, SuFey;  Bailey, Michael;  Warren, Sarah;  Rao, Disha;  Krijgsman, Oscar;  Rozeman, Elisa A.;  Peeper, Daniel;  Blank, Christian U.;  Schumacher, Ton N.;  Butterfield, Lisa H.;  Zelazowska, Monika A.;  McBride, Kevin M.;  Kalluri, Raghu;  Allison, James;  Petitprez, Florent;  Fridman, Wolf Herman;  Sautes-Fridman, Catherine;  Hacohen, Nir;  Rezvani, Katayoun;  Sharma, Padmanee;  Tetzlaff, Michael T.;  Wang, Linghua;  Wargo, Jennifer A.
收藏  |  浏览/下载:37/0  |  提交时间:2020/05/13

Outdoor air pollution adversely affects human health and is estimated to be responsible for five to ten per cent of the total annual premature mortality in the contiguous United States(1-3). Combustion emissions from a variety of sources, such as power generation or road traffic, make a large contribution to harmful air pollutants such as ozone and fine particulate matter (PM2.5)(4). Efforts to mitigate air pollution have focused mainly on the relationship between local emission sources and local air quality(2). Air quality can also be affected by distant emission sources, however, including emissions from neighbouring federal states(5,6). This cross-state exchange of pollution poses additional regulatory challenges. Here we quantify the exchange of air pollution among the contiguous United States, and assess its impact on premature mortality that is linked to increased human exposure to PM2.5 and ozone from seven emission sectors for 2005 to 2018. On average, we find that 41 to 53 per cent of air-quality-related premature mortality resulting from a state'  s emissions occurs outside that state. We also find variations in the cross-state contributions of different emission sectors and chemical species to premature mortality, and changes in these variations over time. Emissions from electric power generation have the greatest cross-state impacts as a fraction of their total impacts, whereas commercial/residential emissions have the smallest. However, reductions in emissions from electric power generation since 2005 have meant that, by 2018, cross-state premature mortality associated with the commercial/residential sector was twice that associated with power generation. In terms of the chemical species emitted, nitrogen oxides and sulfur dioxide emissions caused the most cross-state premature deaths in 2005, but by 2018 primary PM2.5 emissions led to cross-state premature deaths equal to three times those associated with sulfur dioxide emissions. These reported shifts in emission sectors and emission species that contribute to premature mortality may help to guide improvements to air quality in the contiguous United States.


  
Structure of the M2 muscarinic receptor-beta-arrestin complex in a lipid nanodisc 期刊论文
NATURE, 2020, 579 (7798) : 297-+
作者:  Gate, David;  Saligrama, Naresha;  Leventhal, Olivia;  Yang, Andrew C.;  Unger, Michael S.;  Middeldorp, Jinte;  Chen, Kelly;  Lehallier, Benoit;  Channappa, Divya;  De Los Santos, Mark B.;  McBride, Alisha;  Pluvinage, John;  Elahi, Fanny;  Tam, Grace Kyin-Ye;  Kim, Yongha;  Greicius, Michael;  Wagner, Anthony D.;  Aigner, Ludwig;  Galasko, Douglas R.;  Davis, Mark M.;  Wyss-Coray, Tony
收藏  |  浏览/下载:29/0  |  提交时间:2020/07/03

After activation by an agonist, G-protein-coupled receptors (GPCRs) recruit beta-arrestin, which desensitizes heterotrimeric G-protein signalling and promotes receptor endocytosis(1). Additionally, beta-arrestin directly regulates many cell signalling pathways that can induce cellular responses distinct from that of G proteins(2). In contrast to G proteins, for which there are many high-resolution structures in complex with GPCRs, the molecular mechanisms underlying the interaction of beta-arrestin with GPCRs are much less understood. Here we present a cryo-electron microscopy structure of beta-arrestin 1 (beta arr1) in complex with M2 muscarinic receptor (M2R) reconstituted in lipid nanodiscs. The M2R-beta arr1 complex displays a multimodal network of flexible interactions, including binding of the N domain of beta arr1 to phosphorylated receptor residues and insertion of the finger loop of beta arr1 into the M2R seven-transmembrane bundle, which adopts a conformation similar to that in the M2R-heterotrimeric G(o) protein complex(3). Moreover, the cryo-electron microscopy map reveals that the C-edge of beta arr1 engages the lipid bilayer. Through atomistic simulations and biophysical, biochemical and cellular assays, we show that the C-edge is critical for stable complex formation, beta arr1 recruitment, receptor internalization, and desensitization of G-protein activation. Taken together, these data suggest that the cooperative interactions of beta-arrestin with both the receptor and the phospholipid bilayer contribute to its functional versatility.


  
Quantum crystal structure in the 250-kelvin superconducting lanthanum hydride 期刊论文
NATURE, 2020, 578 (7793) : 66-+
作者:  Gate, David;  Saligrama, Naresha;  Leventhal, Olivia;  Yang, Andrew C.;  Unger, Michael S.;  Middeldorp, Jinte;  Chen, Kelly;  Lehallier, Benoit;  Channappa, Divya;  De Los Santos, Mark B.;  McBride, Alisha;  Pluvinage, John;  Elahi, Fanny;  Tam, Grace Kyin-Ye;  Kim, Yongha;  Greicius, Michael;  Wagner, Anthony D.;  Aigner, Ludwig;  Galasko, Douglas R.;  Davis, Mark M.;  Wyss-Coray, Tony
收藏  |  浏览/下载:20/0  |  提交时间:2020/07/03

The discovery of superconductivity at 200 kelvin in the hydrogen sulfide system at high pressures(1) demonstrated the potential of hydrogen-rich materials as high-temperature superconductors. Recent theoretical predictions of rare-earth hydrides with hydrogen cages(2,3) and the subsequent synthesis of LaH10 with a superconducting critical temperature (T-c) of 250 kelvin(4,5) have placed these materials on the verge of achieving the long-standing goal of room-temperature superconductivity. Electrical and X-ray diffraction measurements have revealed a weakly pressure-dependent T-c for LaH10 between 137 and 218 gigapascals in a structure that has a face-centred cubic arrangement of lanthanum atoms(5). Here we show that quantum atomic fluctuations stabilize a highly symmetrical Fm (3) over barm crystal structure over this pressure range. The structure is consistent with experimental findings and has a very large electron-phonon coupling constant of 3.5. Although ab initio classical calculations predict that this Fm (3) over barm structure undergoes distortion at pressures below 230 gigapascals(2,3,) yielding a complex energy landscape, the inclusion of quantum effects suggests that it is the true ground-state structure. The agreement between the calculated and experimental Tc values further indicates that this phase is responsible for the superconductivity observed at 250 kelvin. The relevance of quantum fluctuations calls into question many of the crystal structure predictions that have been made for hydrides within a classical approach and that currently guide the experimental quest for room-temperature superconductivity(6-8). Furthermore, we find that quantum effects are crucial for the stabilization of solids with high electron-phonon coupling constants that could otherwise be destabilized by the large electron-phonon interaction(9), thus reducing the pressures required for their synthesis.


  
Systemic HIV and SIV latency reversal via non-canonical NF-kappa B signalling in vivo 期刊论文
NATURE, 2020, 578 (7793) : 160-+
作者:  Momcilovic, Milica;  Jones, Anthony;  Bailey, Sean T.;  Waldmann, Christopher M.;  Li, Rui;  Lee, Jason T.;  Abdelhady, Gihad;  Gomez, Adrian;  Holloway, Travis;  Schmid, Ernst;  Stout, David;  Fishbein, Michael C.;  Stiles, Linsey;  Dabir, Deepa V.;  Dubinett, Steven M.;  Christofk, Heather;  Shirihai, Orian;  Koehler, Carla M.;  Sadeghi, Saman;  Shackelford, David B.
收藏  |  浏览/下载:22/0  |  提交时间:2020/07/03

Activation of the non-canonical NF-kappa B signalling pathway by AZD5582 results in the induction of HIV and SIV RNA expression in the blood and tissues of antiretroviral-therapy-treated humanized mice and rhesus macaques.


Long-lasting, latently infected resting CD4(+) T cells are the greatest obstacle to obtaining a cure for HIV infection, as these cells can persist despite decades of treatment with antiretroviral therapy (ART). Estimates indicate that more than 70 years of continuous, fully suppressive ART are needed to eliminate the HIV reservoir(1). Alternatively, induction of HIV from its latent state could accelerate the decrease in the reservoir, thus reducing the time to eradication. Previous attempts to reactivate latent HIV in preclinical animal models and in clinical trials have measured HIV induction in the peripheral blood with minimal focus on tissue reservoirs and have had limited effect(2-9). Here we show that activation of the non-canonical NF-kappa B signalling pathway by AZD5582 results in the induction of HIV and SIV RNA expression in the blood and tissues of ART-suppressed bone-marrow-liver-thymus (BLT) humanized mice and rhesus macaques infected with HIV and SIV, respectively. Analysis of resting CD4(+) T cells from tissues after AZD5582 treatment revealed increased SIV RNA expression in the lymph nodes of macaques and robust induction of HIV in almost all tissues analysed in humanized mice, including the lymph nodes, thymus, bone marrow, liver and lung. This promising approach to latency reversal-in combination with appropriate tools for systemic clearance of persistent HIV infection-greatly increases opportunities for HIV eradication.