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A bacteriophage nucleus-like compartment shields DNA from CRISPR nucleases 期刊论文
NATURE, 2020, 577 (7789) : 244-+
作者:  Mendoza, Senen D.;  Nieweglowska, Eliza S.;  Govindarajan, Sutharsan;  Leon, Lina M.;  Berry, Joel D.;  Tiwari, Anika;  Chaikeeratisak, Vorrapon;  Pogliano, Joe;  Agard, David A.;  Bondy-Denomy, Joseph
收藏  |  浏览/下载:17/0  |  提交时间:2020/07/03

All viruses require strategies to inhibit or evade the immune pathways of cells that they infect. The viruses that infect bacteria, bacteriophages (phages), must avoid immune pathways that target nucleic acids, such as CRISPR-Cas and restriction-modification systems, to replicate efficiently(1). Here we show that jumbo phage phi KZ segregates its DNA from immunity nucleases of its host, Pseudomonas aeruginosa, by constructing a proteinaceous nucleus-like compartment. phi KZ is resistant to many immunity mechanisms that target DNA in vivo, including two subtypes of CRISPR-Cas3, Cas9, Cas12a and the restriction enzymes HsdRMS and EcoRI. Cas proteins and restriction enzymes are unable to access the phage DNA throughout the infection, but engineering the relocalization of EcoRI inside the compartment enables targeting of the phage and protection of host cells. Moreover, phi KZ is sensitive to Cas13a-a CRISPR-Cas enzyme that targets RNA-probably owing to phage mRNA localizing to the cytoplasm. Collectively, we propose that Pseudomonas jumbo phages evade a broad spectrum of DNA-targeting nucleases through the assembly of a protein barrier around their genome.


  
Potential circadian effects on translational failure for neuroprotection 期刊论文
NATURE, 2020
作者:  Sakai, Akito;  Minami, Susumu;  Koretsune, Takashi;  Chen, Taishi;  Higo, Tomoya;  Wang, Yangming;  Nomoto, Takuya;  Hirayama, Motoaki;  Miwa, Shinji;  Nishio-Hamane, Daisuke;  Ishii, Fumiyuki;  Arita, Ryotaro;  Nakatsuji, Satoru
收藏  |  浏览/下载:14/0  |  提交时间:2020/07/03

Neuroprotectant strategies that have worked in rodent models of stroke have failed to provide protection in clinical trials. Here we show that the opposite circadian cycles in nocturnal rodents versus diurnal humans(1,2) may contribute to this failure in translation. We tested three independent neuroprotective approaches-normobaric hyperoxia, the free radical scavenger alpha-phenyl-butyl-tert-nitrone (alpha PBN), and the N-methyl-d-aspartic acid (NMDA) antagonist MK801-in mouse and rat models of focal cerebral ischaemia. All three treatments reduced infarction in day-time (inactive phase) rodent models of stroke, but not in night-time (active phase) rodent models of stroke, which match the phase (active, day-time) during which most strokes occur in clinical trials. Laser-speckle imaging showed that the penumbra of cerebral ischaemia was narrower in the active-phase mouse model than in the inactive-phase model. The smaller penumbra was associated with a lower density of terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL)-positive dying cells and reduced infarct growth from 12 to 72 h. When we induced circadian-like cycles in primary mouse neurons, deprivation of oxygen and glucose triggered a smaller release of glutamate and reactive oxygen species, as well as lower activation of apoptotic and necroptotic mediators, in '  active-phase'  than in '  inactive-phase'  rodent neurons. alpha PBN and MK801 reduced neuronal death only in '  inactive-phase'  neurons. These findings suggest that the influence of circadian rhythm on neuroprotection must be considered for translational studies in stroke and central nervous system diseases.


Studies in rats and mice at different times of day suggest that the failure of neuroprotective strategies for stroke in translational studies might be related to the difference in circadian cycles between humans and rodents.


  
poly(UG)-tailed RNAs in genome protection and epigenetic inheritance 期刊论文
NATURE, 2020, 582 (7811) : 283-+
作者:  Raj, Dipak K.;  Das Mohapatra, Alok;  Jnawali, Anup;  Zuromski, Jenna;  Jha, Ambrish;  Cham-Kpu, Gerald;  Sherman, Brett;  Rudlaff, Rachel M.;  Nixon, Christina E.;  Hilton, Nicholas;  Oleinikov, Andrew V.;  Chesnokov, Olga;  Merritt, Jordan;  Pond-Tor, Sunthorn
收藏  |  浏览/下载:19/0  |  提交时间:2020/07/03

Mobile genetic elements threaten genome integrity in all organisms. RDE-3 (also known as MUT-2) is a ribonucleotidyltransferase that is required for transposon silencing and RNA interference in Caenorhabditis elegans(1-4). When tethered to RNAs in heterologous expression systems, RDE-3 can add long stretches of alternating non-templated uridine (U) and guanosine (G) ribonucleotides to the 3 '  termini of these RNAs (designated poly(UG) or pUG tails)(5). Here we show that, in its natural context in C. elegans, RDE-3 adds pUG tails to targets of RNA interference, as well as to transposon RNAs. RNA fragments attached to pUG tails with more than 16 perfectly alternating 3 '  U and G nucleotides become gene-silencing agents. pUG tails promote gene silencing by recruiting RNA-dependent RNA polymerases, which use pUG-tailed RNAs (pUG RNAs) as templates to synthesize small interfering RNAs (siRNAs). Our results show that cycles of pUG RNA-templated siRNA synthesis and siRNA-directed pUG RNA biogenesis underlie double-stranded-RNA-directed transgenerational epigenetic inheritance in the C. elegans germline. We speculate that this pUG RNA-siRNA silencing loop enables parents to inoculate progeny against the expression of unwanted or parasitic genetic elements.


In Caenorhabditis elegans, the ribonucleotidyltransferase RDE-3 adds alternating uridine and guanosine ribonucleotides to the 3 '  termini of RNAs, a key step in RNA interference and thus epigenetic inheritance in the C. elegans germline.


  
Childhood vaccines and antibiotic use in low- and middle-income countries 期刊论文
NATURE, 2020, 581 (7806) : 94-+
作者:  Louca, Stilianos;  Pennell, Matthew W.
收藏  |  浏览/下载:9/0  |  提交时间:2020/07/03

Vaccines may reduce the burden of antimicrobial resistance, in part by preventing infections for which treatment often includes the use of antibiotics(1-4). However, the effects of vaccination on antibiotic consumption remain poorly understood-especially in low- and middle-income countries (LMICs), where the burden of antimicrobial resistance is greatest(5). Here we show that vaccines that have recently been implemented in the World Health Organization'  s Expanded Programme on Immunization reduce antibiotic consumption substantially among children under five years of age in LMICs. By analysing data from large-scale studies of households, we estimate that pneumococcal conjugate vaccines and live attenuated rotavirus vaccines confer 19.7% (95% confidence interval, 3.4-43.4%) and 11.4% (4.0-18.6%) protection against antibiotic-treated episodes of acute respiratory infection and diarrhoea, respectively, in age groups that experience the greatest disease burden attributable to the vaccine-targeted pathogens(6,7). Under current coverage levels, pneumococcal and rotavirus vaccines prevent 23.8 million and 13.6 million episodes of antibiotic-treated illness, respectively, among children under five years of age in LMICs each year. Direct protection resulting from the achievement of universal coverage targets for these vaccines could prevent an additional 40.0 million episodes of antibiotic-treated illness. This evidence supports the prioritization of vaccines within the global strategy to combat antimicrobial resistance(8).


Pneumococcal and rotavirus vaccines have reduced antibiotic consumption substantially among children under five years old in low- and middle-income countries  however, this effect could be doubled if all countries were to implement vaccination programmes and meet universal vaccine coverage targets.


  
Electrical manipulation of a topological antiferromagnetic state 期刊论文
NATURE, 2020, 580 (7805) : 608-+
作者:  Chabon, Jacob J.;  Hamilton, Emily G.;  Kurtz, David M.;  Esfahani, Mohammad S.;  Moding, Everett J.;  Stehr, Henning;  Schroers-Martin, Joseph;  Nabet, Barzin Y.;  Chen, Binbin;  Chaudhuri, Aadel A.;  Liu, Chih Long;  Hui, Angela B.;  Jin, Michael C.;  Azad, Tej D.;  Almanza, Diego;  Jeon, Young-Jun;  Nesselbush, Monica C.;  Keh, Lyron Co Ting;  Bonilla, Rene F.;  Yoo, Christopher H.;  Ko, Ryan B.;  Chen, Emily L.;  Merriott, David J.;  Massion, Pierre P.;  Mansfield, Aaron S.;  Jen, Jin;  Ren, Hong Z.;  Lin, Steven H.;  Costantino, Christina L.;  Burr, Risa;  Tibshirani, Robert;  Gambhir, Sanjiv S.;  Berry, Gerald J.;  Jensen, Kristin C.;  West, Robert B.;  Neal, Joel W.;  Wakelee, Heather A.;  Loo, Billy W., Jr.;  Kunder, Christian A.;  Leung, Ann N.;  Lui, Natalie S.;  Berry, Mark F.;  Shrager, Joseph B.;  Nair, Viswam S.;  Haber, Daniel A.;  Sequist, Lecia V.;  Alizadeh, Ash A.;  Diehn, Maximilian
收藏  |  浏览/下载:36/0  |  提交时间:2020/07/03

Room-temperature electrical switching of a topological antiferromagnetic state in polycrystalline Mn3Sn thin films is demonstrated using the same protocol as that used for conventional ferromagnetic metals.


Electrical manipulation of phenomena generated by nontrivial band topology is essential for the development of next-generation technology using topological protection. A Weyl semimetal is a three-dimensional gapless system that hosts Weyl fermions as low-energy quasiparticles(1-4). It has various exotic properties, such as a large anomalous Hall effect (AHE) and chiral anomaly, which are robust owing to the topologically protected Weyl nodes(1-16). To manipulate such phenomena, a magnetic version of Weyl semimetals would be useful for controlling the locations of Weyl nodes in the Brillouin zone. Moreover, electrical manipulation of antiferromagnetic Weyl metals would facilitate the use of antiferromagnetic spintronics to realize high-density devices with ultrafast operation(17,18). However, electrical control of a Weyl metal has not yet been reported. Here we demonstrate the electrical switching of a topological antiferromagnetic state and its detection by the AHE at room temperature in a polycrystalline thin film(19) of the antiferromagnetic Weyl metal Mn3Sn9,10,12,20, which exhibits zero-field AHE. Using bilayer devices composed of Mn3Sn and nonmagnetic metals, we find that an electrical current density of about 10(10) to 10(11) amperes per square metre induces magnetic switching in the nonmagnetic metals, with a large change in Hall voltage. In addition, the current polarity along the bias field and the sign of the spin Hall angle of the nonmagnetic metals-positive for Pt (ref. (21)), close to 0 for Cu and negative for W (ref. (22))-determines the sign of the Hall voltage. Notably, the electrical switching in the antiferromagnet is achieved with the same protocol as that used for ferromagnetic metals(23,24). Our results may lead to further scientific and technological advances in topological magnetism and antiferromagnetic spintronics.


  
Predators on track for ocean protection 期刊论文
NATURE, 2020, 580 (7801) : 34-34
作者:  Callaway, Ewen
收藏  |  浏览/下载:6/0  |  提交时间:2020/07/03
Tracking of marine predators to protect Southern Ocean ecosystems 期刊论文
NATURE, 2020
作者:  Kim, Eugene;  Kerssemakers, Jacob;  Shaltiel, Indra A.;  Haering, Christian H.;  Dekker, Cees
收藏  |  浏览/下载:19/0  |  提交时间:2020/07/03

Tracking data from 17 marine predator species in the Southern Ocean are used to identify Areas of Ecological Significance, the protection of which could help to mitigate increasing pressures on Southern Ocean ecosystems.


Southern Ocean ecosystems are under pressure from resource exploitation and climate change(1,2). Mitigation requires the identification and protection of Areas of Ecological Significance (AESs), which have so far not been determined at the ocean-basin scale. Here, using assemblage-level tracking of marine predators, we identify AESs for this globally important region and assess current threats and protection levels. Integration of more than 4,000 tracks from 17 bird and mammal species reveals AESs around sub-Antarctic islands in the Atlantic and Indian Oceans and over the Antarctic continental shelf. Fishing pressure is disproportionately concentrated inside AESs, and climate change over the next century is predicted to impose pressure on these areas, particularly around the Antarctic continent. At present, 7.1% of the ocean south of 40 degrees S is under formal protection, including 29% of the total AESs. The establishment and regular revision of networks of protection that encompass AESs are needed to provide long-term mitigation of growing pressures on Southern Ocean ecosystems.


  
Decoy exosomes provide protection against bacterial toxins 期刊论文
NATURE, 2020, 579 (7798) : 260-+
作者:  Park, Jin Suk;  Burckhardt, Christoph J.;  Lazcano, Rossana;  Solis, Luisa M.;  Isogai, Tadamoto;  Li, Linqing;  Chen, Christopher S.;  Gao, Boning;  Minna, John D.;  Bachoo, Robert;  DeBerardinis, Ralph J.;  Danuser, Gaudenz
收藏  |  浏览/下载:14/0  |  提交时间:2020/07/03

The production of pore-forming toxins that disrupt the plasma membrane of host cells is a common virulence strategy for bacterial pathogens such as methicillin-resistant Staphylococcus aureus (MRSA)(1-3). It is unclear, however, whether host species possess innate immune mechanisms that can neutralize pore-forming toxins during infection. We previously showed that the autophagy protein ATG16L1 is necessary for protection against MRSA strains encoding alpha-toxin(4)-a pore-forming toxin that binds the metalloprotease ADAM10 on the surface of a broad range of target cells and tissues(2,5,6). Autophagy typically involves the targeting of cytosolic material to the lysosome for degradation. Here we demonstrate that ATG16L1 and other ATG proteins mediate protection against alpha-toxin through the release of ADAM10 on exosomes-extracellular vesicles of endosomal origin. Bacterial DNA and CpG DNA induce the secretion of ADAM10-bearing exosomes from human cells as well as in mice. Transferred exosomes protect host cells in vitro by serving as scavengers that can bind multiple toxins, and improve the survival of mice infected with MRSA in vivo. These findings indicate that ATG proteins mediate a previously unknown form of defence in response to infection, facilitating the release of exosomes that serve as decoys for bacterially produced toxins.


  
Electrically pumped topological laser with valley edge modes 期刊论文
NATURE, 2020, 578 (7794) : 246-+
作者:  Erickson, Peter;  van Asselt, Harro;  Koplow, Doug;  Lazarus, Michael;  Newell, Peter;  Oreskes, Naomi;  Supran, Geoffrey
收藏  |  浏览/下载:46/0  |  提交时间:2020/07/03

Quantum cascade lasers are compact, electrically pumped light sources in the technologically important mid-infrared and terahertz region of the electromagnetic spectrum(1,2). Recently, the concept of topology(3) has been expanded from condensed matter physics into photonics(4), giving rise to a new type of lasing(5-8) using topologically protected photonic modes that can efficiently bypass corners and defects(4). Previous demonstrations of topological lasers have required an external laser source for optical pumping and have operated in the conventional optical frequency regime(5-8). Here we demonstrate an electrically pumped terahertz quantum cascade laser based on topologically protected valley edge states(9-11). Unlike topological lasers that rely on large-scale features to impart topological protection, our compact design makes use of the valley degree of freedom in photonic crystals(10,11), analogous to two-dimensional gapped valleytronic materials(12). Lasing with regularly spaced emission peaks occurs in a sharp-cornered triangular cavity, even if perturbations are introduced into the underlying structure, owing to the existence of topologically protected valley edge states that circulate around the cavity without experiencing localization. We probe the properties of the topological lasing modes by adding different outcouplers to the topological cavity. The laser based on valley edge states may open routes to the practical use of topological protection in electrically driven laser sources.


  
Microbiota-targeted maternal antibodies protect neonates from enteric infection 期刊论文
NATURE, 2020, 577 (7791) : 543-+
作者:  Zheng, Wen;  Zhao, Wenjing;  Wu, Meng;  Song, Xinyang;  Caro, Florence;  Sun, Ximei;  Gazzaniga, Francesca;  Stefanetti, Giuseppe;  Oh, Sungwhan;  Mekalanos, John J.;  Kasper, Dennis L.
收藏  |  浏览/下载:6/0  |  提交时间:2020/07/03

Although maternal antibodies protect newborn babies from infection(1,2), little is known about how protective antibodies are induced without prior pathogen exposure. Here we show that neonatal mice that lack the capacity to produce IgG are protected from infection with the enteric pathogen enterotoxigenic Escherichia coli by maternal natural IgG antibodies against the maternal microbiota when antibodies are delivered either across the placenta or through breast milk. By challenging pups that were fostered by either maternal antibody-sufficient or antibody-deficient dams, we found that IgG derived from breast milk was crucial for protection against mucosal disease induced by enterotoxigenic E. coli. IgG also provides protection against systemic infection by E. coli. Pups used the neonatal Fc receptor to transfer IgG from milk into serum. The maternal commensal microbiota can induce antibodies that recognize antigens expressed by enterotoxigenic E. coli and other Enterobacteriaceae species. Induction of maternal antibodies against a commensal Pantoea species confers protection against enterotoxigenic E. coli in pups. This role of the microbiota in eliciting protective antibodies to a specific neonatal pathogen represents an important host defence mechanism against infection in neonates.


Neonatal mice are protected against infection with the enteric pathogen enterotoxigenic Escherichia coli by maternally derived natural antibodies as well as by maternal commensal microbiota that induce antibodies that recognize antigens expressed by Enterobacteriaceae.