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山区适应气候变化的机遇 快报文章
资源环境快报,2022年第09期
作者:  李恒吉
Microsoft Word(15Kb)  |  收藏  |  浏览/下载:683/1  |  提交时间:2022/05/17
Climate action  Nature for human and ecosystem health  Sustainable Development  
A developmental landscape of 3D-cultured human pre-gastrulation embryos 期刊论文
NATURE, 2020, 577 (7791) : 537-+
作者:  Xiang, Lifeng;  Yin, Yu;  Zheng, Yun;  Ma, Yanping;  Li, Yonggang;  Zhao, Zhigang;  Guo, Junqiang;  Ai, Zongyong;  Niu, Yuyu;  Duan, Kui;  He, Jingjing;  Ren, Shuchao;  Wu, Dan;  Bai, Yun;  Shang, Zhouchun;  Dai, Xi;  Ji, Weizhi;  Li, Tianqing
收藏  |  浏览/下载:12/0  |  提交时间:2020/07/03

Our understanding of how human embryos develop before gastrulation, including spatial self-organization and cell type ontogeny, remains limited by available two-dimensional technological platforms(1,2) that do not recapitulate the in vivo conditions(3-5). Here we report a three-dimensional (3D) blastocyst-culture system that enables human blastocyst development up to the primitive streak anlage stage. These 3D embryos mimic developmental landmarks and 3D architectures in vivo, including the embryonic disc, amnion, basement membrane, primary and primate unique secondary yolk sac, formation of anterior-posterior polarity and primitive streak anlage. Using single-cell transcriptome profiling, we delineate ontology and regulatory networks that underlie the segregation of epiblast, primitive endoderm and trophoblast. Compared with epiblasts, the amniotic epithelium shows unique and characteristic phenotypes. After implantation, specific pathways and transcription factors trigger the differentiation of cytotrophoblasts, extravillous cytotrophoblasts and syncytiotrophoblasts. Epiblasts undergo a transition to pluripotency upon implantation, and the transcriptome of these cells is maintained until the generation of the primitive streak anlage. These developmental processes are driven by different pluripotency factors. Together, findings from our 3D-culture approach help to determine the molecular and morphogenetic developmental landscape that occurs during human embryogenesis.


A 3D culture system to model human embryonic development, together with single-cell transcriptome profiling, provides insights into the molecular developmental landscape during human post-implantation embryogenesis.


  
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.


  
A dominant autoinflammatory disease caused by non-cleavable variants of RIPK1 期刊论文
NATURE, 2020, 577 (7788) : 109-+
作者:  Tao, Panfeng;  Sun, Jinqiao;  Wu, Zheming;  Wang, Shihao;  Wang, Jun;  Li, Wanjin;  Pan, Heling;  Bai, Renkui;  Zhang, Jiahui;  Wang, Ying;  Lee, Pui Y.;  Ying, Wenjing;  Zhou, Qinhua;  Hou, Jia;  Wang, Wenjie;  Sun, Bijun;  Yang, Mi;  Liu, Danru;  Fang, Ran;  Han, Huan;  Yang, Zhaohui;  Huang, Xin;  Li, Haibo;  Deuitch, Natalie;  Zhang, Yuan;  Dissanayake, Dilan;  Haude, Katrina;  McWalter, Kirsty;  Roadhouse, Chelsea;  MacKenzie, Jennifer J.;  Laxer, Ronald M.;  Aksentijevich, Ivona;  Yu, Xiaomin;  Wang, Xiaochuan;  Yuan, Junying;  Zhou, Qing
收藏  |  浏览/下载:24/0  |  提交时间:2020/07/03

Activation of RIPK1 controls TNF-mediated apoptosis, necroptosis and inflammatory pathways(1). Cleavage of human and mouse RIPK1 after residues D324 and D325, respectively, by caspase-8 separates the RIPK1 kinase domain from the intermediate and death domains. The D325A mutation in mouse RIPK1 leads to embryonic lethality during mouse development(2,3). However, the functional importance of blocking caspase-8-mediated cleavage of RIPK1 on RIPK1 activation in humans is unknown. Here we identify two families with variants in RIPK1 (D324V and D324H) that lead to distinct symptoms of recurrent fevers and lymphadenopathy in an autosomaldominant manner. Impaired cleavage of RIPK1 D324 variants by caspase-8 sensitized patients'  peripheral blood mononuclear cells to RIPK1 activation, apoptosis and necroptosis induced by TNF. The patients showed strong RIPK1-dependent activation of inflammatory signalling pathways and overproduction of inflammatory cytokines and chemokines compared with unaffected controls. Furthermore, we show that expression of the RIPK1 mutants D325V or D325H in mouse embryonic fibroblasts confers not only increased sensitivity to RIPK1 activation-mediated apoptosis and necroptosis, but also induction of pro-inflammatory cytokines such as IL-6 and TNF. By contrast, patient-derived fibroblasts showed reduced expression of RIPK1 and downregulated production of reactive oxygen species, resulting in resistance to necroptosis and ferroptosis. Together, these data suggest that human non-cleavable RIPK1 variants promote activation of RIPK1, and lead to an autoinflammatory disease characterized by hypersensitivity to apoptosis and necroptosis and increased inflammatory response in peripheral blood mononuclear cells, as well as a compensatory mechanism to protect against several pro-death stimuli in fibroblasts.


  
Impaired cell fate through gain-of-function mutations in a chromatin reader 期刊论文
NATURE, 2020, 577 (7788) : 121-+
作者:  Wan, Liling;  Chong, Shasha;  Xuan, Fan;  Liang, Angela;  Cui, Xiaodong;  Gates, Leah;  Carroll, Thomas S.;  Li, Yuanyuan;  Feng, Lijuan;  Chen, Guochao;  Wang, Shu-Ping;  Ortiz, Michael V.;  Daley, Sara K.;  Wang, Xiaolu;  Xuan, Hongwen;  Kentsis, Alex;  Muir, Tom W.;  Roeder, Robert G.;  Li, Haitao;  Li, Wei;  Tjian, Robert;  Wen, Hong;  Allis, C. David
收藏  |  浏览/下载:10/0  |  提交时间:2020/07/03

Modifications of histone proteins have essential roles in normal development and human disease. Recognition of modified histones by '  reader'  proteins is a key mechanism that mediates the function of histone modifications, but how the dysregulation of these readers might contribute to disease remains poorly understood. We previously identified the ENL protein as a reader of histone acetylation via its YEATS domain, linking it to the expression of cancer-driving genes in acute leukaemia1. Recurrent hotspot mutations have been found in the ENL YEATS domain in Wilms tumour2,3, the most common type of paediatric kidney cancer. Here we show, using human and mouse cells, that these mutations impair cell-fate regulation by conferring gain-of-function in chromatin recruitment and transcriptional control. ENL mutants induce gene-expression changes that favour a premalignant cell fate, and, in an assay for nephrogenesis using murine cells, result in undifferentiated structures resembling those observed in human Wilms tumour. Mechanistically, although bound to largely similar genomic loci as the wild-type protein, ENL mutants exhibit increased occupancy at a subset of targets, leading to a marked increase in the recruitment and activity of transcription elongation machinery that enforces active transcription from target loci. Furthermore, ectopically expressed ENL mutants exhibit greater self-association and form discrete and dynamic nuclear puncta that are characteristic of biomolecular hubs consisting of local high concentrations of regulatory factors. Such mutation-driven ENL self-association is functionally linked to enhanced chromatin occupancy and gene activation. Collectively, our findings show that hotspot mutations in a chromatinreader domain drive self-reinforced recruitment, derailing normal cell-fate control during development and leading to an oncogenic outcome.


  
Structure of nevanimibe-bound tetrameric human ACAT1 期刊论文
NATURE, 2020, 581 (7808) : 339-U214
作者:  Ma, Xiyu;  Claus, Lucas A. N.;  Leslie, Michelle E.;  Tao, Kai;  Wu, Zhiping;  Liu, Jun;  Yu, Xiao;  Li, Bo;  Zhou, Jinggeng;  Savatin, Daniel V.;  Peng, Junmin;  Tyler, Brett M.;  Heese, Antje;  Russinova, Eugenia;  He, Ping;  Shan, Libo
收藏  |  浏览/下载:28/0  |  提交时间:2020/07/03

The structure of human ACAT1 in complex with the inhibitor nevanimibe is resolved by cryo-electron microscopy.


Cholesterol is an essential component of mammalian cell membranes, constituting up to 50% of plasma membrane lipids. By contrast, it accounts for only 5% of lipids in the endoplasmic reticulum (ER)(1). The ER enzyme sterol O-acyltransferase 1 (also named acyl-coenzyme A:cholesterol acyltransferase, ACAT1) transfers a long-chain fatty acid to cholesterol to form cholesteryl esters that coalesce into cytosolic lipid droplets. Under conditions of cholesterol overload, ACAT1 maintains the low cholesterol concentration of the ER and thereby has an essential role in cholesterol homeostasis(2,3). ACAT1 has also been implicated in Alzheimer'  s disease(4), atherosclerosis(5) and cancers(6). Here we report a cryo-electron microscopy structure of human ACAT1 in complex with nevanimibe(7), an inhibitor that is in clinical trials for the treatment of congenital adrenal hyperplasia. The ACAT1 holoenzyme is a tetramer that consists of two homodimers. Each monomer contains nine transmembrane helices (TMs), six of which (TM4-TM9) form a cavity that accommodates nevanimibe and an endogenous acyl-coenzyme A. This cavity also contains a histidine that has previously been identified as essential for catalytic activity(8). Our structural data and biochemical analyses provide a physical model to explain the process of cholesterol esterification, as well as details of the interaction between nevanimibe and ACAT1, which may help to accelerate the development of ACAT1 inhibitors to treat related diseases.


  
Structures of human pannexin 1 reveal ion pathways and mechanism of gating 期刊论文
NATURE, 2020
作者:  Krause, David W.;  Hoffmann, Simone;  Hu, Yaoming;  Wible, John R.;  Rougier, Guillermo W.;  Kirk, E. Christopher;  Groenke, Joseph R.;  Rogers, Raymond R.;  Rossie, James B.;  Schultz, Julia A.;  Evans, Alistair R.;  von Koenigswald, Wighart;  Rahantarisoa, Lydia J.
收藏  |  浏览/下载:9/0  |  提交时间:2020/07/03

Cryo-electron microscopy structures of the ATP-permeable channel pannexin 1 reveal a gating mechanism involving multiple distinct ion-conducting pathways.


Pannexin 1 (PANX1) is an ATP-permeable channel with critical roles in a variety of physiological functions such as blood pressure regulation(1), apoptotic cell clearance(2) and human oocyte development(3). Here we present several structures of human PANX1 in a heptameric assembly at resolutions of up to 2.8 angstrom, including an apo state, a caspase-7-cleaved state and a carbenoxolone-bound state. We reveal a gating mechanism that involves two ion-conducting pathways. Under normal cellular conditions, the intracellular entry of the wide main pore is physically plugged by the C-terminal tail. Small anions are conducted through narrow tunnels in the intracellular domain. These tunnels connect to the main pore and are gated by a long linker between the N-terminal helix and the first transmembrane helix. During apoptosis, the C-terminal tail is cleaved by caspase, allowing the release of ATP through the main pore. We identified a carbenoxolone-binding site embraced by W74 in the extracellular entrance and a role for carbenoxolone as a channel blocker. We identified a gap-junction-like structure using a glycosylation-deficient mutant, N255A. Our studies provide a solid foundation for understanding the molecular mechanisms underlying the channel gating and inhibition of PANX1 and related large-pore channels.


  
Hair-bearing human skin generated entirely from pluripotent stem cells 期刊论文
NATURE, 2020
作者:  von Appen, Alexander;  LaJoie, Dollie;  Johnson, Isabel E.;  Trnka, Michael J.;  Pick, Sarah M.;  Burlingame, Alma L.;  Ullman, Katharine S.;  Frost, Adam
收藏  |  浏览/下载:52/0  |  提交时间:2020/07/03

Skin organoids generated in vitro from human pluripotent stem cells form complex, multilayered skin tissue with hair follicles, sebaceous glands and neural circuitry, and integrate with endogenous skin when grafted onto immunocompromised mice.


The skin is a multilayered organ, equipped with appendages (that is, follicles and glands), that is critical for regulating body temperature and the retention of bodily fluids, guarding against external stresses and mediating the sensation of touch and pain(1,2). Reconstructing appendage-bearing skin in cultures and in bioengineered grafts is a biomedical challenge that has yet to be met(3-9). Here we report an organoid culture system that generates complex skin from human pluripotent stem cells. We use stepwise modulation of the transforming growth factor beta (TGF beta) and fibroblast growth factor (FGF) signalling pathways to co-induce cranial epithelial cells and neural crest cells within a spherical cell aggregate. During an incubation period of 4-5 months, we observe the emergence of a cyst-like skin organoid composed of stratified epidermis, fat-rich dermis and pigmented hair follicles that are equipped with sebaceous glands. A network of sensory neurons and Schwann cells form nerve-like bundles that target Merkel cells in organoid hair follicles, mimicking the neural circuitry associated with human touch. Single-cell RNA sequencing and direct comparison to fetal specimens suggest that the skin organoids are equivalent to the facial skin of human fetuses in the second trimester of development. Moreover, we show that skin organoids form planar hair-bearing skin when grafted onto nude mice. Together, our results demonstrate that nearly complete skin can self-assemble in vitro and be used to reconstitute skin in vivo. We anticipate that our skin organoids will provide a foundation for future studies of human skin development, disease modelling and reconstructive surgery.


  
Deciphering human macrophage development at single-cell resolution 期刊论文
NATURE, 2020
作者:  Oberst, Polina;  Fievre, Sabine;  Baumann, Natalia;  Concetti, Cristina;  Bartolini, Giorgia;  Jabaudon, Denis
收藏  |  浏览/下载:20/0  |  提交时间:2020/07/03

Macrophages are the first cells of the nascent immune system to emerge during embryonic development. In mice, embryonic macrophages infiltrate developing organs, where they differentiate symbiotically into tissue-resident macrophages (TRMs)(1). However, our understanding of the origins and specialization of macrophages in human embryos is limited. Here we isolated CD45(+) haematopoietic cells from human embryos at Carnegie stages 11 to 23 and subjected them to transcriptomic profiling by single-cell RNA sequencing, followed by functional characterization of a population of CD45(+)CD34(+)CD44(+) yolk sac-derived myeloid-biased progenitors (YSMPs) by single-cell culture. We also mapped macrophage heterogeneity across multiple anatomical sites and identified diverse subsets, including various types of embryonic TRM (in the head, liver, lung and skin). We further traced the specification trajectories of TRMs from either yolk sac-derived primitive macrophages or YSMP-derived embryonic liver monocytes using both transcriptomic and developmental staging information, with a focus on microglia. Finally, we evaluated the molecular similarities between embryonic TRMs and their adult counterparts. Our data represent a comprehensive characterization of the spatiotemporal dynamics of early macrophage development during human embryogenesis, providing a reference for future studies of the development and function of human TRMs.


Single-cell RNA sequencing of haematopoietic cells from human embryos at different developmental stages sheds light on the development and specification of macrophages in different tissues.


  
Measuring and forecasting progress towards the education-related SDG targets 期刊论文
NATURE, 2020, 580 (7805) : 636-+
作者:  Hindell, Mark A.;  Reisinger, Ryan R.;  Ropert-Coudert, Yan;  Huckstadt, Luis A.;  Trathan, Philip N.;  Bornemann, Horst;  Charrassin, Jean-Benoit;  Chown, Steven L.;  Costa, Daniel P.;  Danis, Bruno;  Lea, Mary-Anne;  Thompson, David;  Torres, Leigh G.;  Van de Putte, Anton P.
收藏  |  浏览/下载:17/0  |  提交时间:2020/07/03

Education is a key dimension of well-being and a crucial indicator of development(1-4). The Sustainable Development Goals (SDGs) prioritize progress in education, with a new focus on inequality(5-7). Here we model the within-country distribution of years of schooling, and use this model to explore educational inequality since 1970 and to forecast progress towards the education-related 2030 SDG targets. We show that although the world is largely on track to achieve near-universal primary education by 2030, substantial challenges remain in the completion rates for secondary and tertiary education. Globally, the gender gap in schooling had nearly closed by 2018 but gender disparities remained acute in parts of sub-Saharan Africa, and North Africa and the Middle East. It is predicted that, by 2030, females will have achieved significantly higher educational attainment than males in 18 countries. Inequality in education reached a peak globally in 2017 and is projected to decrease steadily up to 2030. The distributions and inequality metrics presented here represent a framework that can be used to track the progress of each country towards the SDG targets and the level of inequality over time. Reducing educational inequality is one way to promote a fairer distribution of human capital and the development of more equitable human societies.


Great progress toward the education-related SDG targets has been made  however, global estimates of within-country distributions of education reveal gender disparities and high levels of total inequality in many parts of the world.