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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.


  
Microbial signatures in tumours and blood 期刊论文
NATURE, 2020, 579 (7800) : 502-503
作者:  Goodman, Russell P.;  Markhard, Andrew L.;  Shah, Hardik;  Sharma, Rohit;  Skinner, Owen S.;  Clish, Clary B.;  Deik, Amy;  Patgiri, Anupam;  Hsu, Yu-Han H.;  Masia, Ricard;  Noh, Hye Lim;  Suk, Sujin;  Goldberger, Olga;  Hirschhorn, Joel N.;  Yellen, Gary;  Kim, Jason K.;  Mootha, Vamsi K.
收藏  |  浏览/下载:22/0  |  提交时间:2020/07/03

Microbiome signatures as putative cancer diagnostics.


Analysis of nucleic-acid sequences from human cancers, along with samples from adjacent tissue and blood, reveals the presence of microorganisms in tumours and blood across cancers.


  
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).


  
Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I 期刊论文
NATURE, 2020, 581 (7806) : 100-+
作者:  Waszak, Sebastian M.;  Robinson, Giles W.;  Gudenas, Brian L.;  Smith, Kyle S.;  Forget, Antoine;  Kojic, Marija;  Garcia-Lopez, Jesus;  Hadley, Jennifer;  Hamilton, Kayla V.;  Indersie, Emilie;  Buchhalter, Ivo;  Kerssemakers, Jules;  Jager, Natalie;  Sharma, Tanvi;  Rausch, Tobias;  Kool, Marcel;  Sturm, Dominik;  Jones, David T. W.;  Vasilyeva, Aksana;  Tatevossian, Ruth G.;  Neale, Geoffrey;  Lombard, Berangere;  Loew, Damarys;  Nakitandwe, Joy;  Rusch, Michael;  Bowers, Daniel C.;  Bendel, Anne;  Partap, Sonia;  Chintagumpala, Murali;  Crawford, John;  Gottardo, Nicholas G.;  Smith, Amy;  Dufour, Christelle;  Rutkowski, Stefan;  Eggen, Tone;  Wesenberg, Finn;  Kjaerheim, Kristina;  Feychting, Maria;  Lannering, Birgitta;  Schuz, Joachim;  Johansen, Christoffer;  Andersen, Tina V.;  Roosli, Martin;  Kuehni, Claudia E.;  Grotzer, Michael;  Remke, Marc;  Puget, Stephanie;  Pajtler, Kristian W.;  Milde, Till;  Witt, Olaf;  Ryzhova, Marina;  Korshunov, Andrey;  Orr, Brent A.;  Ellison, David W.;  Brugieres, Laurence;  Lichter, Peter;  Nichols, Kim E.;  Gajjar, Amar;  Wainwright, Brandon J.;  Ayrault, Olivier;  Korbel, Jan O.;  Northcott, Paul A.;  Pfister, Stefan M.
收藏  |  浏览/下载:38/0  |  提交时间:2020/07/03

Immune evasion is a major obstacle for cancer treatment. Common mechanisms of evasion include impaired antigen presentation caused by mutations or loss of heterozygosity of the major histocompatibility complex class I (MHC-I), which has been implicated in resistance to immune checkpoint blockade (ICB) therapy(1-3). However, in pancreatic ductal adenocarcinoma (PDAC), which is resistant to most therapies including ICB4, mutations that cause loss of MHC-I are rarely found(5) despite the frequent downregulation of MHC-I expression(6-8). Here we show that, in PDAC, MHC-I molecules are selectively targeted for lysosomal degradation by an autophagy-dependent mechanism that involves the autophagy cargo receptor NBR1. PDAC cells display reduced expression of MHC-I at the cell surface and instead demonstrate predominant localization within autophagosomes and lysosomes. Notably, inhibition of autophagy restores surface levels of MHC-I and leads to improved antigen presentation, enhanced anti-tumour T cell responses and reduced tumour growth in syngeneic host mice. Accordingly, the anti-tumour effects of autophagy inhibition are reversed by depleting CD8(+) T cells or reducing surface expression of MHC-I. Inhibition of autophagy, either genetically or pharmacologically with chloroquine, synergizes with dual ICB therapy (anti-PD1 and anti-CTLA4 antibodies), and leads to an enhanced anti-tumour immune response. Our findings demonstrate a role for enhanced autophagy or lysosome function in immune evasion by selective targeting of MHC-I molecules for degradation, and provide a rationale for the combination of autophagy inhibition and dual ICB therapy as a therapeutic strategy against PDAC.


Inhibition of the autophagy-lysosome system upregulates surface expression of MHC class I proteins and enhances antigen presentation, and evokes a potent anti-tumour immune response that is mediated by CD8(+) T cells.


  
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.


  
Cryo-EM structure of SWI/SNF complex bound to a nucleosome 期刊论文
NATURE, 2020
作者:  Hang, Saiyu;  Paik, Donggi;  Yao, Lina;  Kim, Eunha;  Trinath, Jamma;  Lu, Jingping;  Ha, Soyoung;  Nelson, Brandon N.;  Kelly, Samantha P.;  Wu, Lin;  Zheng, Ye;  Longman, Randy S.;  Rastinejad, Fraydoon;  Devlin, A. Sloan;  Krout, Michael R.;  Fischbach, Michael A.;  Littman, Dan R.;  Huh, Jun R.
收藏  |  浏览/下载:7/0  |  提交时间:2020/07/03

The chromatin-remodelling complex SWI/SNF is highly conserved and has critical roles in various cellular processes, including transcription and DNA-damage repair(1,2). It hydrolyses ATP to remodel chromatin structure by sliding and evicting histone octamers(3-8), creating DNA regions that become accessible to other essential factors. However, our mechanistic understanding of the remodelling activity is hindered by the lack of a high-resolution structure of complexes from this family. Here we report the cryo-electron microscopy structure of Saccharomyces cerevisiae SWI/SNF bound to a nucleosome, at near-atomic resolution. In the structure, the actin-related protein (Arp) module is sandwiched between the ATPase and the rest of the complex, with the Snf2 helicase-SANT associated (HSA) domain connecting all modules. The body contains an assembly scaffold composed of conserved subunits Snf12 (also known as SMARCD or BAF60), Snf5 (also known as SMARCB1, BAF47 or INI1) and an asymmetric dimer of Swi3 (also known as SMARCC, BAF155 or BAF170). Another conserved subunit, Swi1 (also known as ARID1 or BAF250), resides in the core of SWI/SNF, acting as a molecular hub. We also observed interactions between Snf5 and the histones at the acidic patch, which could serve as an anchor during active DNA translocation. Our structure enables us to map and rationalize a subset of cancer-related mutations in the human SWI/SNF complex and to propose a model for how SWI/SNF recognizes and remodels the +1 nucleosome to generate nucleosome-depleted regions during gene activation(9).


The cryo-electron microscopy structure of the yeast SWI/SNF complex bound to a nucleosome substrate provides insights into the chromatin-remodelling function of this family of protein complexes and suggests mechanisms by which the mutated proteins may cause cancer.


  
Spontaneous gyrotropic electronic order in a transition-metal dichalcogenide 期刊论文
NATURE, 2020, 578 (7796) : 545-+
作者:  Kum, Hyun S.;  Lee, Hyungwoo;  Kim, Sungkyu;  Lindemann, Shane;  Kong, Wei;  Qiao, Kuan;  Chen, Peng;  Irwin, Julian;  Lee, June Hyuk;  Xie, Saien;  Subramanian, Shruti;  Shim, Jaewoo;  Bae, Sang-Hoon;  Choi, Chanyeol;  Ranno, Luigi;  Seo, Seungju;  Lee, Sangho;  Bauer, Jackson;  Li, Huashan;  Lee, Kyusang;  Robinson, Joshua A.;  Ross, Caroline A.;  Schlom, Darrell G.;  Rzchowski, Mark S.;  Eom, Chang-Beom;  Kim, Jeehwan
收藏  |  浏览/下载:10/0  |  提交时间:2020/07/03

Chirality is ubiquitous in nature, and populations of opposite chiralities are surprisingly asymmetric at fundamental levels(1,2). Examples range from parity violation in the subatomic weak force to homochirality in biomolecules. The ability to achieve chirality-selective synthesis (chiral induction) is of great importance in stereochemistry, molecular biology and pharmacology(2). In condensed matter physics, a crystalline electronic system is geometrically chiral when it lacks mirror planes, space-inversion centres or rotoinversion axes(1). Typically, geometrical chirality is predefined by the chiral lattice structure of a material, which is fixed on formation of the crystal. By contrast, in materials with gyrotropic order(3-6), electrons spontaneously organize themselves to exhibit macroscopic chirality in an originally achiral lattice. Although such order-which has been proposed as the quantum analogue of cholesteric liquid crystals-has attracted considerable interest(3-15), no clear observation or manipulation of gyrotropic order has been achieved so far. Here we report the realization of optical chiral induction and the observation of a gyrotropically ordered phase in the transition-metal dichalcogenide semimetal 1T-TiSe2. We show that shining mid-infrared circularly polarized light on 1T-TiSe2 while cooling it below the critical temperature leads to the preferential formation of one chiral domain. The chirality of this state is confirmed by the measurement of an out-of-plane circular photogalvanic current, the direction of which depends on the optical induction. Although the role of domain walls requires further investigation with local probes, the methodology demonstrated here can be applied to realize and control chiral electronic phases in other quantum materials(4,16).


Optical chiral induction and spontaneous gyrotropic electronic order are realized in the transition-metal chalcogenide 1T-TiSe2 by using illumination with mid-infrared circularly polarized light and simultaneous cooling below the critical temperature.


  
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.


  
The role of Olfr78 in the breathing circuit of mice Reply 期刊论文
NATURE, 2018, 561 (7724) : E41-E41
作者:  Chang, Andy J.;  Kim, Noah S.;  Hireed, Homza;  de Arce, Alex Diaz;  Ortega, Fabian E.;  Riegler, Johannes;  Madison, Daniel V.;  Krasnow, Mark A.
收藏  |  浏览/下载:6/0  |  提交时间:2019/11/27