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Frequent mutations that converge on the NFKBIZ pathway in ulcerative colitis 期刊论文
NATURE, 2020, 577 (7789) : 260-+
作者:  Kakiuchi, Nobuyuki;  Yoshida, Kenichi;  Uchino, Motoi;  Kihara, Takako;  Akaki, Kotaro;  Inoue, Yoshikage;  Kawada, Kenji;  Nagayama, Satoshi;  Yokoyama, Akira;  Yamamoto, Shuji;  Matsuura, Minoru;  Horimatsu, Takahiro;  Hirano, Tomonori;  Goto, Norihiro;  Takeuchi, Yasuhide;  Ochi, Yotaro;  Shiozawa, Yusuke;  Kogure, Yasunori;  Watatani, Yosaku;  Fujii, Yoichi;  Kim, Soo Ki;  Kon, Ayana;  Kataoka, Keisuke;  Yoshizato, Tetsuichi;  Nakagawa, Masahiro M.;  Yoda, Akinori;  Nanya, Yasuhito;  Makishima, Hideki;  Shiraishi, Yuichi;  Chiba, Kenichi;  Tanaka, Hiroko;  Sanada, Masashi;  Sugihara, Eiji;  Sato, Taka-aki;  Maruyama, Takashi;  Miyoshi, Hiroyuki;  Taketo, Makoto Mark;  Oishi, Jun;  Inagaki, Ryosaku;  Ueda, Yutaka;  Okamoto, Shinya;  Okajima, Hideaki;  Sakai, Yoshiharu;  Sakurai, Takaki;  Haga, Hironori;  Hirota, Seiichi;  Ikeuchi, Hiroki;  Nakase, Hiroshi;  Marusawa, Hiroyuki;  Chiba, Tsutomu;  Takeuchi, Osamu;  Miyano, Satoru;  Seno, Hiroshi;  Ogawa, Seishi
收藏  |  浏览/下载:78/0  |  提交时间:2020/07/03

Chronic inflammation is accompanied by recurring cycles of tissue destruction and repair and is associated with an increased risk of cancer(1-3). However, how such cycles affect the clonal composition of tissues, particularly in terms of cancer development, remains unknown. Here we show that in patients with ulcerative colitis, the inflamed intestine undergoes widespread remodelling by pervasive clones, many of which are positively selected by acquiring mutations that commonly involve the NFKBIZ, TRAF3IP2, ZC3H12A, PIGR and HNRNPF genes and are implicated in the downregulation of IL-17 and other pro-inflammatory signals. Mutational profiles vary substantially between colitis-associated cancer and non-dysplastic tissues in ulcerative colitis, which indicates that there are distinct mechanisms of positive selection in both tissues. In particular, mutations in NFKBIZ are highly prevalent in the epithelium of patients with ulcerative colitis but rarely found in both sporadic and colitis-associated cancer, indicating that NFKBIZ-mutant cells are selected against during colorectal carcinogenesis. In further support of this negative selection, we found that tumour formation was significantly attenuated in Nfkbiz-mutant mice and cell competition was compromised by disruption of NFKBIZ in human colorectal cancer cells. Our results highlight common and discrete mechanisms of clonal selection in inflammatory tissues, which reveal unexpected cancer vulnerabilities that could potentially be exploited for therapeutics in colorectal cancer.


  
Infrared spectroscopy finally sees the light 期刊论文
NATURE, 2020, 577 (7788) : 34-35
作者:  Barth, Andreas
收藏  |  浏览/下载:0/0  |  提交时间:2020/07/03
Population flow drives spatio-temporal distribution of COVID-19 in China 期刊论文
NATURE, 2020
作者:  Fernandez, Diego Carlos;  Komal, Ruchi;  Langel, Jennifer;  Ma, Jun;  Duy, Phan Q.;  Penzo, Mario A.;  Zhao, Haiqing;  Hattar, Samer
收藏  |  浏览/下载:69/0  |  提交时间:2020/07/03

Sudden, large-scale and diffuse human migration can amplify localized outbreaks of disease into widespread epidemics(1-4). Rapid and accurate tracking of aggregate population flows may therefore be epidemiologically informative. Here we use 11,478,484 counts of mobile phone data from individuals leaving or transiting through the prefecture of Wuhan between 1 January and 24 January 2020 as they moved to 296 prefectures throughout mainland China. First, we document the efficacy of quarantine in ceasing movement. Second, we show that the distribution of population outflow from Wuhan accurately predicts the relative frequency and geographical distribution of infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) until 19 February 2020, across mainland China. Third, we develop a spatio-temporal '  risk source'  model that leverages population flow data (which operationalize the risk that emanates from epidemic epicentres) not only to forecast the distribution of confirmed cases, but also to identify regions that have a high risk of transmission at an early stage. Fourth, we use this risk source model to statistically derive the geographical spread of COVID-19 and the growth pattern based on the population outflow from Wuhan  the model yields a benchmark trend and an index for assessing the risk of community transmission of COVID-19 over time for different locations. This approach can be used by policy-makers in any nation with available data to make rapid and accurate risk assessments and to plan the allocation of limited resources ahead of ongoing outbreaks.


Modelling of population flows in China enables the forecasting of the distribution of confirmed cases of COVID-19 and the identification of areas at high risk of SARS-CoV-2 transmission at an early stage.


  
Base-pair conformational switch modulates miR-34a targeting of Sirt1 mRNA 期刊论文
NATURE, 2020, 583 (7814) : 139-+
作者:  Muniz, Juan A.;  Barberena, Diego;  Lewis-Swan, Robert J.;  Young, Dylan J.;  Cline, Julia R. K.;  Rey, Ana Maria;  Thompson, James K.
收藏  |  浏览/下载:22/0  |  提交时间:2020/07/03

MicroRNAs (miRNAs) regulate the levels of translation of messenger RNAs (mRNAs). At present, the major parameter that can explain the selection of the target mRNA and the efficiency of translation repression is the base pairing between the '  seed'  region of the miRNA and its counterpart mRNA(1). Here we use R-1 rho relaxation-dispersion nuclear magnetic resonance(2) and molecular simulations(3) to reveal a dynamic switch-based on the rearrangement of a single base pair in the miRNA-mRNA duplex-that elongates a weak five-base-pair seed to a complete seven-base-pair seed. This switch also causes coaxial stacking of the seed and supplementary helix fitting into human Argonaute 2 protein (Ago2), reminiscent of an active state in prokaryotic Ago(4,5). Stabilizing this transient state leads to enhanced repression of the target mRNA in cells, revealing the importance of this miRNA-mRNA structure. Our observations tie together previous findings regarding the stepwise miRNA targeting process from an initial '  screening'  state to an '  active'  state, and unveil the role of the RNA duplex beyond the seed in Ago2.


Repression of a messenger RNA by a cognate microRNA depends not only on complementary base pairing, but also on the rearrangement of a single base pair, producing a conformation that fits better within the human Ago2 protein.


  
Variability in the analysis of a single neuroimaging dataset by many teams 期刊论文
NATURE, 2020
作者:  Liu, Jifeng;  Soria, Roberto;  Zheng, Zheng;  Zhang, Haotong;  Lu, Youjun;  Wang, Song;  Yuan, Hailong
收藏  |  浏览/下载:22/0  |  提交时间:2020/07/03

Data analysis workflows in many scientific domains have become increasingly complex and flexible. Here we assess the effect of this flexibility on the results of functional magnetic resonance imaging by asking 70 independent teams to analyse the same dataset, testing the same 9 ex-ante hypotheses(1). The flexibility of analytical approaches is exemplified by the fact that no two teams chose identical workflows to analyse the data. This flexibility resulted in sizeable variation in the results of hypothesis tests, even for teams whose statistical maps were highly correlated at intermediate stages of the analysis pipeline. Variation in reported results was related to several aspects of analysis methodology. Notably, a meta-analytical approach that aggregated information across teams yielded a significant consensus in activated regions. Furthermore, prediction markets of researchers in the field revealed an overestimation of the likelihood of significant findings, even by researchers with direct knowledge of the dataset(2-5). Our findings show that analytical flexibility can have substantial effects on scientific conclusions, and identify factors that may be related to variability in the analysis of functional magnetic resonance imaging. The results emphasize the importance of validating and sharing complex analysis workflows, and demonstrate the need for performing and reporting multiple analyses of the same data. Potential approaches that could be used to mitigate issues related to analytical variability are discussed.


The results obtained by seventy different teams analysing the same functional magnetic resonance imaging dataset show substantial variation, highlighting the influence of analytical choices and the importance of sharing workflows publicly and performing multiple analyses.


  
Submicrosecond entangling gate between trapped ions via Rydberg interaction 期刊论文
NATURE, 2020, 580 (7803) : 345-+
作者:  Chatterjee, Sourav;  Guidi, Mara;  Seeberger, Peter H.;  Gilmore, Kerry
收藏  |  浏览/下载:16/0  |  提交时间:2020/07/03

Generating quantum entanglement in large systems on timescales much shorter than the coherence time is key to powerful quantum simulation and computation. Trapped ions are among the most accurately controlled and best isolated quantum systems(1) with low-error entanglement gates operated within tens of microseconds using the vibrational motion of few-ion crystals(2,3). To exceed the level of complexity tractable by classical computers the main challenge is to realize fast entanglement operations in crystals made up of many ions (large ion crystals)(4). The strong dipole-dipole interactions in polar molecule(5) and Rydberg atom(6,7) systems allow much faster entangling gates, yet stable state-independent confinement comparable with trapped ions needs to be demonstrated in these systems(8). Here we combine the benefits of these approaches: we report a two-ion entangling gate with 700-nanosecond gate time that uses the strong dipolar interaction between trapped Rydberg ions, which we use to produce a Bell state with 78 per cent fidelity. The sources of gate error are identified and a total error of less than 0.2 per cent is predicted for experimentally achievable parameters. Furthermore, we predict that residual coupling to motional modes contributes an approximate gate error of 10(-4) in a large ion crystal of 100 ions. This provides a way to speed up and scale up trapped-ion quantum computers and simulators substantially.


  
Jennifer Clack (1947-2020) Obituary 期刊论文
NATURE, 2020, 580 (7805) : 587-587
作者:  Ferry, Georgina
收藏  |  浏览/下载:0/0  |  提交时间:2020/07/03

Palaeontologist who described how vertebrates moved from water to land.


Palaeontologist who described how vertebrates moved from water to land.


  
Germline Elongator mutations in Sonic Hedgehog medulloblastoma 期刊论文
NATURE, 2020, 580 (7803) : 396-+
作者:  Helmrich, S.;  Arias, A.;  Lochead, G.;  Wintermantel, T. M.;  Buchhold, M.;  Diehl, S.;  Whitlock, S.
收藏  |  浏览/下载:15/0  |  提交时间:2020/07/03

Cancer genomics has revealed many genes and core molecular processes that contribute to human malignancies, but the genetic and molecular bases of many rare cancers remains unclear. Genetic predisposition accounts for 5 to 10% of cancer diagnoses in children(1,2), and genetic events that cooperate with known somatic driver events are poorly understood. Pathogenic germline variants in established cancer predisposition genes have been recently identified in 5% of patients with the malignant brain tumour medulloblastoma(3). Here, by analysing all protein-coding genes, we identify and replicate rare germline loss-of-function variants across ELP1 in 14% of paediatric patients with the medulloblastoma subgroup Sonic Hedgehog (MBSHH). ELP1 was the most common medulloblastoma predisposition gene and increased the prevalence of genetic predisposition to 40% among paediatric patients with MBSHH. Parent-offspring and pedigree analyses identified two families with a history of paediatric medulloblastoma. ELP1-associated medulloblastomas were restricted to the molecular SHH alpha subtype(4) and characterized by universal biallelic inactivation of ELP1 owing to somatic loss of chromosome arm 9q. Most ELP1-associated medulloblastomas also exhibited somatic alterations in PTCH1, which suggests that germline ELP1 loss-of-function variants predispose individuals to tumour development in combination with constitutive activation of SHH signalling. ELP1 is the largest subunit of the evolutionarily conserved Elongator complex, which catalyses translational elongation through tRNA modifications at the wobble (U-34) position(5,6). Tumours from patients with ELP1-associated MBSHH were characterized by a destabilized Elongator complex, loss of Elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response, consistent with loss of protein homeostasis due to Elongator deficiency in model systems(7-9). Thus, genetic predisposition to proteome instability may be a determinant in the pathogenesis of paediatric brain cancers. These results support investigation of the role of protein homeostasis in other cancer types and potential for therapeutic interference.


  
COVID-19: research after the pandemic 期刊论文
NATURE, 2020, 580 (7802) : 185-185
作者:  Triantis, Kostas A.;  Matthews, Thomas J.
收藏  |  浏览/下载:5/0  |  提交时间:2020/07/03
Mott and generalized Wigner crystal states in WSe2/WS2 moire superlattices 期刊论文
NATURE, 2020, 579 (7799) : 359-+
作者:  Yuan, Jie;  Chang, Si-Yuan;  Yin, Shi-Gang;  Liu, Zhi-Yang;  Cheng, Xiu;  Liu, Xi-Juan;  Jiang, Qiang;  Gao, Ge;  Lin, De-Ying;  Kang, Xin-Lei;  Ye, Shi-Wei;  Chen, Zheng;  Yin, Jiang-An;  Hao, Pei;  Jiang, Lubin;  Cai, Shi-Qing
收藏  |  浏览/下载:50/0  |  提交时间:2020/07/03

Strongly correlated insulating Mott and generalized Wigner phases are detected in WSe2/WS2 moire superlattices, and their electrical properties and excited spin states are studied using an optical technique.


Moire superlattices can be used to engineer strongly correlated electronic states in two-dimensional van der Waals heterostructures, as recently demonstrated in the correlated insulating and superconducting states observed in magic-angle twisted-bilayer graphene and ABC trilayer graphene/boron nitride moire superlattices(1-4). Transition metal dichalcogenide moire heterostructures provide another model system for the study of correlated quantum phenomena(5) because of their strong light-matter interactions and large spin-orbit coupling. However, experimental observation of correlated insulating states in this system is challenging with traditional transport techniques. Here we report the optical detection of strongly correlated phases in semiconducting WSe2/WS2 moire superlattices. We use a sensitive optical detection technique and reveal a Mott insulator state at one hole per superlattice site and surprising insulating phases at 1/3 and 2/3 filling of the superlattice, which we assign to generalized Wigner crystallization on the underlying lattice(6-11). Furthermore, the spin-valley optical selection rules(12-14) of transition metal dichalcogenide heterostructures allow us to optically create and investigate low-energy excited spin states in the Mott insulator. We measure a very long spin relaxation lifetime of many microseconds in the Mott insulating state, orders of magnitude longer than that of charge excitations. Our studies highlight the value of using moire superlattices beyond graphene to explore correlated physics.