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Localization and delocalization of light in photonic moire lattices 期刊论文
NATURE, 2020, 577 (7788) : 42-+
作者:  Wang, Peng;  Zheng, Yuanlin;  Chen, Xianfeng;  Huang, Changming;  Kartashov, Yaroslav V.;  Torner, Lluis;  Konotop, Vladimir V.;  Ye, Fangwei
收藏  |  浏览/下载:27/0  |  提交时间:2020/07/03

Moire lattices consist of two superimposed identical periodic structures with a relative rotation angle. Moire lattices have several applications in everyday life, including artistic design, the textile industry, architecture, image processing, metrology and interferometry. For scientific studies, they have been produced using coupled graphene-hexagonal boron nitride monolayers(1,2), graphene-graphene layers(3,4) and graphene quasicrystals on a silicon carbide surface(5). The recent surge of interest in moire lattices arises from the possibility of exploring many salient physical phenomena in such systems  examples include commensurable-incommensurable transitions and topological defects(2), the emergence of insulating states owing to band flattening(3,6), unconventional superconductivity(4) controlled by the rotation angle(7,8), the quantum Hall effect(9), the realization of non-Abelian gauge potentials(10) and the appearance of quasicrystals at special rotation angles(11). A fundamental question that remains unexplored concerns the evolution of waves in the potentials defined by moire lattices. Here we experimentally create two-dimensional photonic moire lattices, which-unlike their material counterparts-have readily controllable parameters and symmetry, allowing us to explore transitions between structures with fundamentally different geometries (periodic, general aperiodic and quasicrystal). We observe localization of light in deterministic linear lattices that is based on flatband physics(6), in contrast to previous schemes based on light diffusion in optical quasicrystals(12), where disorder is required(13) for the onset of Anderson localization(14) (that is, wave localization in random media). Using commensurable and incommensurable moire patterns, we experimentally demonstrate the twodimensional localization-delocalization transition of light. Moire lattices may feature an almost arbitrary geometry that is consistent with the crystallographic symmetry groups of the sublattices, and therefore afford a powerful tool for controlling the properties of light patterns and exploring the physics of periodic-aperiodic phase transitions and two-dimensional wavepacket phenomena relevant to several areas of science, including optics, acoustics, condensed matter and atomic physics.


  
Mouse models of neutropenia reveal progenitor-stage-specific defects 期刊论文
NATURE, 2020
作者:  Lombardo, Umberto;  Iriarte, Jose;  Hilbert, Lautaro;  Ruiz-Perez, Javier;  Capriles, Jose M.;  Veit, Heinz
收藏  |  浏览/下载:31/0  |  提交时间:2020/07/03

Advances in genetics and sequencing have identified a plethora of disease-associated and disease-causing genetic alterations. To determine causality between genetics and disease, accurate models for molecular dissection are required  however, the rapid expansion of transcriptional populations identified through single-cell analyses presents a major challenge for accurate comparisons between mutant and wild-type cells. Here we generate mouse models of human severe congenital neutropenia (SCN) using patient-derived mutations in the GFI1 transcription factor. To determine the effects of SCN mutations, we generated single-cell references for granulopoietic genomic states with linked epitopes(1), aligned mutant cells to their wild-type equivalents and identified differentially expressed genes and epigenetic loci. We find that GFI1-target genes are altered sequentially, as cells go through successive states of differentiation. These insights facilitated the genetic rescue of granulocytic specification but not post-commitment defects in innate immune effector function, and underscore the importance of evaluating the effects of mutations and therapy within each relevant cell state.


Mouse models of severe congenital neutropenia using patient-derived mutations in the GFI1 locus are used to determine the mechanisms by which the disease progresses.


  
Dynamic RNA acetylation revealed by quantitative cross-evolutionary mapping 期刊论文
NATURE, 2020, 583 (7817) : 638-+
作者:  Lin, Yiheng;  Leibrandt, David R.;  Leibfriedz, Dietrich;  Chou, Chin-wen
收藏  |  浏览/下载:42/0  |  提交时间:2020/07/03

A method termed ac(4)C-seq is introduced for the transcriptome-wide mapping of the RNA modificationN(4)-acetylcytidine, revealing widespread temperature-dependent acetylation that facilitates thermoadaptation in hyperthermophilic archaea.


N-4-acetylcytidine (ac(4)C) is an ancient and highly conserved RNA modification that is present on tRNA and rRNA and has recently been investigated in eukaryotic mRNA(1-3). However, the distribution, dynamics and functions of cytidine acetylation have yet to be fully elucidated. Here we report ac(4)C-seq, a chemical genomic method for the transcriptome-wide quantitative mapping of ac(4)C at single-nucleotide resolution. In human and yeast mRNAs, ac(4)C sites are not detected but can be induced-at a conserved sequence motif-via the ectopic overexpression of eukaryotic acetyltransferase complexes. By contrast, cross-evolutionary profiling revealed unprecedented levels of ac(4)C across hundreds of residues in rRNA, tRNA, non-coding RNA and mRNA from hyperthermophilic archaea. (AcC)-C-4 is markedly induced in response to increases in temperature, and acetyltransferase-deficient archaeal strains exhibit temperature-dependent growth defects. Visualization of wild-type and acetyltransferase-deficient archaeal ribosomes by cryo-electron microscopy provided structural insights into the temperature-dependent distribution of ac(4)C and its potential thermoadaptive role. Our studies quantitatively define the ac(4)C landscape, providing a technical and conceptual foundation for elucidating the role of this modification in biology and disease(4-6).


  
Oncometabolites suppress DNA repair by disrupting local chromatin signalling 期刊论文
NATURE, 2020
作者:  Zhang, Xu;  Lei, Bo;  Yuan, Yuan;  Zhang, Li;  Hu, Lu;  Jin, Sen;  Kang, Bilin;  Liao, Xuebin;  Sun, Wenzhi;  Xu, Fuqiang;  Zhong, Yi;  Hu, Ji;  Qi, Hai
收藏  |  浏览/下载:50/0  |  提交时间:2020/07/03

Metabolites that are elevated in tumours inhibit the lysine demethylase KDM4B, resulting in aberrant hypermethylation of histone 3 lysine 9 and decreased homology-dependent DNA repair.


Deregulation of metabolism and disruption of genome integrity are hallmarks of cancer(1). Increased levels of the metabolites 2-hydroxyglutarate, succinate and fumarate occur in human malignancies owing to somatic mutations in the isocitrate dehydrogenase-1 or -2 (IDH1 or IDH2) genes, or germline mutations in the fumarate hydratase (FH) and succinate dehydrogenase genes (SDHA, SDHB, SDHC and SDHD), respectively(2-4). Recent work has made an unexpected connection between these metabolites and DNA repair by showing that they suppress the pathway of homology-dependent repair (HDR)(5,6) and confer an exquisite sensitivity to inhibitors of poly (ADP-ribose) polymerase (PARP) that are being tested in clinical trials. However, the mechanism by which these oncometabolites inhibit HDR remains poorly understood. Here we determine the pathway by which these metabolites disrupt DNA repair. We show that oncometabolite-induced inhibition of the lysine demethylase KDM4B results in aberrant hypermethylation of histone 3 lysine 9 (H3K9) at loci surrounding DNA breaks, masking a local H3K9 trimethylation signal that is essential for the proper execution of HDR. Consequently, recruitment of TIP60 and ATM, two key proximal HDR factors, is substantially impaired at DNA breaks, with reduced end resection and diminished recruitment of downstream repair factors. These findings provide a mechanistic basis for oncometabolite-induced HDR suppression and may guide effective strategies to exploit these defects for therapeutic gain.


  
Plant 22-nt siRNAs mediate translational repression and stress adaptation 期刊论文
NATURE, 2020, 581 (7806) : 89-+
作者:  Roulis, Manolis;  Kaklamanos, Aimilios;  Schernthanner, Marina;  Bielecki, Piotr;  Zhao, Jun;  Kaffe, Eleanna;  Frommelt, Laura-Sophie;  Qu, Rihao;  Knapp, Marlene S.;  Henriques, Ana;  Chalkidi, Niki;  Koliaraki, Vasiliki;  Jiao, Jing;  Brewer, J. Richard;  Bacher, Maren;  Blackburn, Holly N.;  Zhao, Xiaoyun;  Breyer, Richard M.;  Aidinis, Vassilis;  Jain, Dhanpat;  Su, Bing;  Herschman, Harvey R.;  Kluger, Yuval;  Kollias, George;  Flavell, Richard A.
收藏  |  浏览/下载:54/0  |  提交时间:2020/07/03

Characterization of 22-nucleotide short interfering RNAs in plants finds that they accumulate in response to environmental stress, causing translational repression, inhibition of plant growth and enhanced stress responses.


Small interfering RNAs (siRNAs) are essential for proper development and immunity in eukaryotes(1). Plants produce siRNAs with lengths of 21, 22 or 24 nucleotides. The 21- and 24-nucleotide species mediate cleavage of messenger RNAs and DNA methylation(2,3), respectively, but the biological functions of the 22-nucleotide siRNAs remain unknown. Here we report the identification and characterization of a group of endogenous 22-nucleotide siRNAs that are generated by the DICER-LIKE 2 (DCL2) protein in plants. When cytoplasmic RNA decay and DCL4 are deficient, the resulting massive accumulation of 22-nucleotide siRNAs causes pleiotropic growth disorders, including severe dwarfism, meristem defects and pigmentation. Notably, two genes that encode nitrate reductases-NIA1 and NIA2-produce nearly half of the 22-nucleotide siRNAs. Production of 22-nucleotide siRNAs triggers the amplification of gene silencing and induces translational repression both gene specifically and globally. Moreover, these 22-nucleotide siRNAs preferentially accumulate upon environmental stress, especially those siRNAs derived from NIA1/2, which act to restrain translation, inhibit plant growth and enhance stress responses. Thus, our research uncovers the unique properties of 22-nucleotide siRNAs, and reveals their importance in plant adaptation to environmental stresses.


  
LEM2 phase separation promotes ESCRT-mediated nuclear envelope reformation 期刊论文
NATURE, 2020
作者:  Deshaies, Raymond J.
收藏  |  浏览/下载:29/0  |  提交时间:2020/07/03

Following cell division, phase separation of the transmembrane adaptor LEM2 ensures that the ESCRT machinery remodels microtubules and seals the nuclear envelope.


During cell division, remodelling of the nuclear envelope enables chromosome segregation by the mitotic spindle(1). The reformation of sealed nuclei requires ESCRTs (endosomal sorting complexes required for transport) and LEM2, a transmembrane ESCRT adaptor(2-4). Here we show how the ability of LEM2 to condense on microtubules governs the activation of ESCRTs and coordinated spindle disassembly. The LEM motif of LEM2 binds BAF, conferring on LEM2 an affinity for chromatin(5,6), while an adjacent low-complexity domain (LCD) promotes LEM2 phase separation. A proline-arginine-rich sequence within the LCD binds to microtubules and targets condensation of LEM2 to spindle microtubules that traverse the nascent nuclear envelope. Furthermore, the winged-helix domain of LEM2 activates the ESCRT-II/ESCRT-III hybrid protein CHMP7 to form co-oligomeric rings. Disruption of these events in human cells prevented the recruitment of downstream ESCRTs, compromised spindle disassembly, and led to defects in nuclear integrity and DNA damage. We propose that during nuclear reassembly LEM2 condenses into a liquid-like phase and coassembles with CHMP7 to form a macromolecular O-ring seal at the confluence between membranes, chromatin and the spindle. The properties of LEM2 described here, and the homologous architectures of related inner nuclear membrane proteins(7,8), suggest that phase separation may contribute to other critical envelope functions, including interphase repair(8-13) and chromatin organization(14-17).


  
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:51/0  |  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.


  
AIM2 inflammasome surveillance of DNA damage shapes neurodevelopment 期刊论文
NATURE, 2020, 580 (7805) : 647-+
作者:  Okada, Tatsuaki;  Fukuhara, Tetsuya;  Tanaka, Satoshi;  Taguchi, Makoto;  Arai, Takehiko;  Senshu, Hiroki;  Sakatani, Naoya;  Shimaki, Yuri;  Demura, Hirohide;  Ogawa, Yoshiko;  Suko, Kentaro;  Sekiguchi, Tomohiko;  Kouyama, Toru;  Takita, Jun;  Matsunaga, Tsuneo;  Imamura, Takeshi;  Wada, Takehiko;  Hasegawa, Sunao;  Helbert, Joern;  Mueller, Thomas G.;  Hagermann, Axel;  Biele, Jens;  Grott, Matthias;  Hamm, Maximilian;  Delbo, Marco;  Hirata, Naru;  Hirata, Naoyuki;  Yamamoto, Yukio;  Sugita, Seiji;  Namiki, Noriyuki;  Kitazato, Kohei;  Arakawa, Masahiko;  Tachibana, Shogo;  Ikeda, Hitoshi;  Ishiguro, Masateru;  Wada, Koji;  Honda, Chikatoshi;  Honda, Rie;  Ishihara, Yoshiaki;  Matsumoto, Koji;  Matsuoka, Moe;  Michikami, Tatsuhiro;  Miura, Akira;  Morota, Tomokatsu;  Noda, Hirotomo;  Noguchi, Rina;  Ogawa, Kazunori;  Shirai, Kei;  Tatsumi, Eri;  Yabuta, Hikaru;  Yokota, Yasuhiro;  Yamada, Manabu;  Abe, Masanao;  Hayakawa, Masahiko;  Iwata, Takahiro;  Ozaki, Masanobu;  Yano, Hajime;  Hosoda, Satoshi;  Mori, Osamu;  Sawada, Hirotaka;  Shimada, Takanobu;  Takeuchi, Hiroshi;  Tsukizaki, Ryudo;  Fujii, Atsushi;  Hirose, Chikako;  Kikuchi, Shota;  Mimasu, Yuya;  Ogawa, Naoko;  Ono, Go;  Takahashi, Tadateru;  Takei, Yuto;  Yamaguchi, Tomohiro;  Yoshikawa, Kent;  Terui, Fuyuto;  Saiki, Takanao;  Nakazawa, Satoru;  Yoshikawa, Makoto;  Watanabe, Seiichiro;  Tsuda, Yuichi
收藏  |  浏览/下载:48/0  |  提交时间:2020/07/03

The sensing of DNA damage by the AIM2 inflammasome promotes the death of central nervous system cells and is required for normal brain development.


Neurodevelopment is characterized by rapid rates of neural cell proliferation and differentiation followed by massive cell death in which more than half of all recently generated brain cells are pruned back. Large amounts of DNA damage, cellular debris, and by-products of cellular stress are generated during these neurodevelopmental events, all of which can potentially activate immune signalling. How the immune response to this collateral damage influences brain maturation and function remains unknown. Here we show that the AIM2 inflammasome contributes to normal brain development and that disruption of this immune sensor of genotoxic stress leads to behavioural abnormalities. During infection, activation of the AIM2 inflammasome in response to double-stranded DNA damage triggers the production of cytokines as well as a gasdermin-D-mediated form of cell death known as pyroptosis(1-4). We observe pronounced AIM2 inflammasome activation in neurodevelopment and find that defects in this sensor of DNA damage result in anxiety-related behaviours in mice. Furthermore, we show that the AIM2 inflammasome contributes to central nervous system (CNS) homeostasis specifically through its regulation of gasdermin-D, and not via its involvement in the production of the cytokines IL-1 and/or IL-18. Consistent with a role for this sensor of genomic stress in the purging of genetically compromised CNS cells, we find that defective AIM2 inflammasome signalling results in decreased neural cell death both in response to DNA damage-inducing agents and during neurodevelopment. Moreover, mutations in AIM2 lead to excessive accumulation of DNA damage in neurons as well as an increase in the number of neurons that incorporate into the adult brain. Our findings identify the inflammasome as a crucial player in establishing a properly formed CNS through its role in the removal of genetically compromised cells.


  
Mechanisms and therapeutic implications of hypermutation in gliomas 期刊论文
NATURE, 2020, 580 (7804) : 517-+
作者:  Feng, Kaibo;  Quevedo, Raundi E.;  Kohrt, Jeffrey T.;  Oderinde, Martins S.;  Reilly, Usa;  White, M. Christina
收藏  |  浏览/下载:44/0  |  提交时间:2020/07/03

A high tumour mutational burden (hypermutation) is observed in some gliomas(1-5)  however, the mechanisms by which hypermutation develops and whether it predicts the response to immunotherapy are poorly understood. Here we comprehensively analyse the molecular determinants of mutational burden and signatures in 10,294 gliomas. We delineate two main pathways to hypermutation: a de novo pathway associated with constitutional defects in DNA polymerase and mismatch repair (MMR) genes, and a more common post-treatment pathway, associated with acquired resistance driven by MMR defects in chemotherapy-sensitive gliomas that recur after treatment with the chemotherapy drug temozolomide. Experimentally, the mutational signature of post-treatment hypermutated gliomas was recapitulated by temozolomide-induced damage in cells with MMR deficiency. MMR-deficient gliomas were characterized by a lack of prominent T cell infiltrates, extensive intratumoral heterogeneity, poor patient survival and a low rate of response to PD-1 blockade. Moreover, although bulk analyses did not detect microsatellite instability in MMR-deficient gliomas, single-cell whole-genome sequencing analysis of post-treatment hypermutated glioma cells identified microsatellite mutations. These results show that chemotherapy can drive the acquisition of hypermutated populations without promoting a response to PD-1 blockade and supports the diagnostic use of mutational burden and signatures in cancer.


Temozolomide therapy seems to lead to mismatch repair deficiency and hypermutation in gliomas, but not to an increase in response to immunotherapy.


  
Observation of topologically enabled unidirectional guided resonances 期刊论文
NATURE, 2020, 580 (7804) : 467-+
作者:  Wang, Renjing;  Wang, Shengliu;  Dhar, Ankita;  Peralta, Christopher;  Pavletich, Nikola P.
收藏  |  浏览/下载:21/0  |  提交时间:2020/07/03

Unidirectional radiation is important for various optoelectronic applications, such as lasers, grating couplers and optical antennas. However, almost all existing unidirectional emitters rely on the use of materials or structures that forbid outgoing waves-that is, mirrors, which are often bulky, lossy and difficult to fabricate. Here we theoretically propose and experimentally demonstrate a class of resonances in photonic crystal slabs that radiate only towards one side of the slab, with no mirror placed on the other side. These resonances, which we name '  unidirectional guided resonances'  , are found to be topological in nature: they emerge when a pair of half-integer topological charges(1-3) in the polarization field bounce into each other in momentum space. We experimentally demonstrate unidirectional guided resonances in the telecommunication regime by achieving single-side radiative quality factors as high as 1.6 x 10(5). We further demonstrate their topological nature through far-field polarimetry measurements. Our work represents a characteristic example of applying topological principles(4,5) to control optical fields and could lead to energy-efficient grating couplers and antennas for light detection and ranging.


Unidirectional radiation is achieved in a photonic crystal slab without the use of mirrors by merging a pair of topological defects carrying half-integer charges.