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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.


  
IL-17a promotes sociability in mouse models of neurodevelopmental disorders 期刊论文
NATURE, 2020, 577 (7789) : 249-+
作者:  Reed, Michael Douglas;  Yim, Yeong Shin;  Wimmer, Ralf D.;  Kim, Hyunju;  Ryu, Changhyeon;  Welch, Gwyneth Margaret;  Andina, Matias;  King, Hunter Oren;  Waisman, Ari;  Halassa, Michael M.;  Huh, Jun R.;  Choi, Gloria B.
收藏  |  浏览/下载:11/0  |  提交时间:2020/07/03

A subset of children with autism spectrum disorder appear to show an improvement in their behavioural symptoms during the course of a fever, a sign of systemic inflammation(1,2). Here we elucidate the molecular and neural mechanisms that underlie the beneficial effects of inflammation on social behaviour deficits in mice. We compared an environmental model of neurodevelopmental disorders in which mice were exposed to maternal immune activation (MIA) during embryogenesis(3,4) with mouse models that are genetically deficient for contactin-associated protein-like 2 (Cntnap2)(5), fragile X mental retardation-1 (Fmr1)(6) or Sh3 and multiple ankyrin repeat domains 3 (Shank3)(7). We establish that the social behaviour deficits in offspring exposed to MIA can be temporarily rescued by the inflammatory response elicited by the administration of lipopolysaccharide (LPS). This behavioural rescue was accompanied by a reduction in neuronal activity in the primary somatosensory cortex dysgranular zone (S1DZ), the hyperactivity of which was previously implicated in the manifestation of behavioural phenotypes associated with offspring exposed to MIA(8). By contrast, we did not observe an LPS-induced rescue of social deficits in the monogenic models. We demonstrate that the differences in responsiveness to the LPS treatment between the MIA and the monogenic models emerge from differences in the levels of cytokine production. LPS treatment in monogenic mutant mice did not induce amounts of interleukin-17a (IL-17a) comparable to those induced in MIA offspring  bypassing this difference by directly delivering IL-17a into S1DZ was sufficient to promote sociability in monogenic mutant mice as well as in MIA offspring. Conversely, abrogating the expression of IL-17 receptor subunit a (IL-17Ra) in the neurons of the S1DZ eliminated the ability of LPS to reverse the sociability phenotypes in MIA offspring. Our data support a neuroimmune mechanism that underlies neurodevelopmental disorders in which the production of IL-17a during inflammation can ameliorate the expression of social behaviour deficits by directly affecting neuronal activity in the central nervous system.


  
Ruthenium isotope vestige of Earth's pre-late-veneer mantle preserved in Archaean rocks 期刊论文
NATURE, 2020, 579 (7798) : 240-+
作者:  Abadie, Valerie;  Kim, Sangman M.;  Lejeune, Thomas;  Palanski, Brad A.;  Ernest, Jordan D.;  Tastet, Olivier;  Voisine, Jordan;  Discepolo, Valentina;  Marietta, Eric, V;  Hawash, Mohamed B. F.;  Ciszewski, Cezary;  Bouziat, Romain;  Panigrahi, Kaushik;  Horwath, Irina;  Zurenski, Matthew A.;  Lawrence, Ian;  Dumaine, Anne;  Yotova, Vania;  Grenier, Jean-Christophe;  Murray, Joseph A.;  Khosla, Chaitan;  Barreiro, Luis B.;  Jabri, Bana
收藏  |  浏览/下载:31/0  |  提交时间:2020/05/13

The accretion of volatile-rich material from the outer Solar System represents a crucial prerequisite for Earth to develop oceans and become a habitable planet(1-4). However, the timing of this accretion remains controversial(5-8). It has been proposed that volatile elements were added to Earth by the late accretion of a late veneer consisting of carbonaceous-chondrite-like material after core formation had ceased(6,9,10). This view could not be reconciled with the ruthenium (Ru) isotope composition of carbonaceous chondrites(5,11), which is distinct from that of the modern mantle(12), or of any known meteorite group(5). As a possible solution, Earth'  s pre-late-veneer mantle could already have contained a fraction of Ru that was not fully extracted by core formation(13). The presence of such pre-late-veneer Ru can only be established if its isotope composition is distinct from that of the modern mantle. Here we report the first high-precision, mass-independent Ru isotope compositions for Eoarchaean ultramafic rocks from southwest Greenland, which display a relative Ru-100 excess of 22 parts per million compared with the modern mantle value. This Ru-100 excess indicates that the source of the Eoarchaean rocks already contained a substantial fraction of Ru before the accretion of the late veneer. By 3.7 billion years ago, the mantle beneath southwest Greenland had not yet fully equilibrated with late accreted material. Otherwise, no Ru isotopic difference relative to the modern mantle would be observed. If constraints from other highly siderophile elements besides Ru are also considered(14), the composition of the modern mantle can only be reconciled if the late veneer contained substantial amounts of carbonaceous-chondrite-like materials with their characteristic Ru-100 deficits. These data therefore relax previous constraints on the late veneer and are consistent with volatile-rich material from the outer Solar System being delivered to Earth during late accretion.


  
A lysosomal switch triggers proteostasis renewal in the immortal C. elegans germ lineage (vol 551, pg 629, 2017) 期刊论文
NATURE, 2020, 580 (7802) : E5-E5
作者:  Lu, Zhihao;  Zou, Jianling;  Li, Shuang;  Topper, Michael J.;  Tao, Yong;  Zhang, Hao;  Jiao, Xi;  Xie, Wenbing;  Kong, Xiangqian;  Vaz, Michelle;  Li, Huili;  Cai, Yi;  Xia, Limin;  Huang, Peng;  Rodgers, Kristen;  Lee, Beverly;  Riemer, Joanne B.;  Day, Chi-Ping;  Yen, Ray-Whay Chiu;  Cui, Ying;  Wang, Yujiao;  Wang, Yanni;  Zhang, Weiqiang;  Easwaran, Hariharan;  Hulbert, Alicia;  Kim, KiBem;  Juergens, Rosalyn A.;  Yang, Stephen C.;  Battafarano, Richard J.;  Bush, Errol L.;  Broderick, Stephen R.;  Cattaneo, Stephen M.;  Brahmer, Julie R.;  Rudin, Charles M.;  Wrangle, John;  Mei, Yuping;  Kim, Young J.;  Zhang, Bin;  Wang, Ken Kang-Hsin;  Forde, Patrick M.;  Margolick, Joseph B.;  Nelkin, Barry D.;  Zahnow, Cynthia A.;  Pardoll, Drew M.;  Housseau, Franck;  Baylin, Stephen B.;  Shen, Lin;  Brock, Malcolm V.
收藏  |  浏览/下载:27/0  |  提交时间:2020/07/03
Nightside condensation of iron in an ultrahot giant exoplanet 期刊论文
NATURE, 2020, 580 (7805) : 597-+
作者:  Lu, Zhihao;  Zou, Jianling;  Li, Shuang;  Topper, Michael J.;  Tao, Yong;  Zhang, Hao;  Jiao, Xi;  Xie, Wenbing;  Kong, Xiangqian;  Vaz, Michelle;  Li, Huili;  Cai, Yi;  Xia, Limin;  Huang, Peng;  Rodgers, Kristen;  Lee, Beverly;  Riemer, Joanne B.;  Day, Chi-Ping;  Yen, Ray-Whay Chiu;  Cui, Ying;  Wang, Yujiao;  Wang, Yanni;  Zhang, Weiqiang;  Easwaran, Hariharan;  Hulbert, Alicia;  Kim, KiBem;  Juergens, Rosalyn A.;  Yang, Stephen C.;  Battafarano, Richard J.;  Bush, Errol L.;  Broderick, Stephen R.;  Cattaneo, Stephen M.;  Brahmer, Julie R.;  Rudin, Charles M.;  Wrangle, John;  Mei, Yuping;  Kim, Young J.;  Zhang, Bin;  Wang, Ken Kang-Hsin;  Forde, Patrick M.;  Margolick, Joseph B.;  Nelkin, Barry D.;  Zahnow, Cynthia A.;  Pardoll, Drew M.;  Housseau, Franck;  Baylin, Stephen B.;  Shen, Lin;  Brock, Malcolm V.
收藏  |  浏览/下载:58/0  |  提交时间:2020/07/03

Ultrahot giant exoplanets receive thousands of times Earth'  s insolation(1,2). Their high-temperature atmospheres (greater than 2,000 kelvin) are ideal laboratories for studying extreme planetary climates and chemistry(3-5). Daysides are predicted to be cloud-free, dominated by atomic species(6) and much hotter than nightsides(5,7,8). Atoms are expected to recombine into molecules over the nightside(9), resulting in different day and night chemistries. Although metallic elements and a large temperature contrast have been observed(10-14), no chemical gradient has been measured across the surface of such an exoplanet. Different atmospheric chemistry between the day-to-night ('  evening'  ) and night-to-day ('  morning'  ) terminators could, however, be revealed as an asymmetric absorption signature during transit(4,7,15). Here we report the detection of an asymmetric atmospheric signature in the ultrahot exoplanet WASP-76b. We spectrally and temporally resolve this signature using a combination of high-dispersion spectroscopy with a large photon-collecting area. The absorption signal, attributed to neutral iron, is blueshifted by -11 +/- 0.7 kilometres per second on the trailing limb, which can be explained by a combination of planetary rotation and wind blowing from the hot dayside(16). In contrast, no signal arises from the nightside close to the morning terminator, showing that atomic iron is not absorbing starlight there. We conclude that iron must therefore condense during its journey across the nightside.


Absorption lines of iron in the dayside atmosphere of an ultrahot giant exoplanet disappear after travelling across the nightside, showing that the iron has condensed during its travel.


  
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.


  
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:19/0  |  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.


  
Locally renewing resident synovial macrophages provide a protective barrier for the joint 期刊论文
NATURE, 2019, 572 (7771) : 670-+
作者:  Culemann, Stephan;  Grueneboom, Anika;  Angel Nicolas-Avila, Jose;  Weidner, Daniela;  Laemmle, Katrin Franziska;  Rothe, Tobias;  Quintana, Juan A.;  Kirchner, Philipp;  Krljanac, Branislav;  Eberhardt, Martin;  Ferrazzi, Fulvia;  Kretzschmar, Elke;  Schicht, Martin;  Fischer, Kim;  Gelse, Kolja;  Faas, Maria;  Pfeifle, Rene;  Ackermann, Jochen A.;  Pachowsky, Milena;  Renner, Nina;  Simon, David;  Haseloff, Reiner F.;  Ekici, Arif B.;  Baeuerle, Tobias;  Blasig, Ingolf E.;  Vera, Julio;  Voehringer, David;  Kleyer, Arnd;  Paulsen, Friedrich;  Schett, Georg;  Hidalgo, Andres;  Kroenke, Gerhard
收藏  |  浏览/下载:10/0  |  提交时间:2019/11/27