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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:12/0  |  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.


  
HBO1 is required for the maintenance of leukaemia stem cells 期刊论文
NATURE, 2020, 577 (7789) : 266-+
作者:  MacPherson, Laura;  Anokye, Juliana;  Yeung, Miriam M.;  Lam, Enid Y. N.;  Chan, Yih-Chih;  Weng, Chen-Fang;  Yeh, Paul;  Knezevic, Kathy;  Butler, Miriam S.;  Hoegl, Annabelle;  Chan, Kah-Lok;  Burr, Marian L.;  Gearing, Linden J.;  Willson, Tracy;  Liu, Joy;  Choi, Jarny;  Yang, Yuqing;  Bilardi, Rebecca A.;  Falk, Hendrik;  Nghi Nguyen;  Stupple, Paul A.;  Peat, Thomas S.;  Zhang, Ming;  de Silva, Melanie;  Carrasco-Pozo, Catalina;  Avery, Vicky M.;  Khoo, Poh Sim;  Dolezal, Olan;  Dennis, Matthew L.;  Nuttall, Stewart;  Surjadi, Regina;  Newman, Janet;  Ren, Bin;  Leaver, David J.;  Sun, Yuxin;  Baell, Jonathan B.;  Dovey, Oliver;  Vassiliou, George S.;  Grebien, Florian;  Dawson, Sarah-Jane;  Street, Ian P.;  Monahan, Brendon J.;  Burns, Christopher J.;  Choudhary, Chunaram;  Blewitt, Marnie E.;  Voss, Anne K.;  Thomas, Tim;  Dawson, Mark A.
收藏  |  浏览/下载:19/0  |  提交时间:2020/07/03

Acute myeloid leukaemia (AML) is a heterogeneous disease characterized by transcriptional dysregulation that results in a block in differentiation and increased malignant self-renewal. Various epigenetic therapies aimed at reversing these hallmarks of AML have progressed into clinical trials, but most show only modest efficacy owing to an inability to effectively eradicate leukaemia stem cells (LSCs)(1). Here, to specifically identify novel dependencies in LSCs, we screened a bespoke library of small hairpin RNAs that target chromatin regulators in a unique ex vivo mouse model of LSCs. We identify the MYST acetyltransferase HBO1 (also known as KAT7 or MYST2) and several known members of the HBO1 protein complex as critical regulators of LSC maintenance. Using CRISPR domain screening and quantitative mass spectrometry, we identified the histone acetyltransferase domain of HBO1 as being essential in the acetylation of histone H3 at K14. H3 acetylated at K14 (H3K14ac) facilitates the processivity of RNA polymerase II to maintain the high expression of key genes (including Hoxa9 and Hoxa10) that help to sustain the functional properties of LSCs. To leverage this dependency therapeutically, we developed a highly potent small-molecule inhibitor of HBO1 and demonstrate its mode of activity as a competitive analogue of acetyl-CoA. Inhibition of HBO1 phenocopied our genetic data and showed efficacy in a broad range of human cell lines and primary AML cells from patients. These biological, structural and chemical insights into a therapeutic target in AML will enable the clinical translation of these findings.


  
A metabolic pathway for bile acid dehydroxylation by the gut microbiome 期刊论文
NATURE, 2020
作者:  Zhong, Miao;  Tran, Kevin;  Min, Yimeng;  Wang, Chuanhao;  Wang, Ziyun;  Dinh, Cao-Thang;  De Luna, Phil;  Yu, Zongqian;  Rasouli, Armin Sedighian;  Brodersen, Peter;  Sun, Song;  Voznyy, Oleksandr;  Tan, Chih-Shan;  Askerka, Mikhail;  Che, Fanglin;  Liu, Min;  Seifitokaldani, Ali;  Pang, Yuanjie;  Lo, Shen-Chuan;  Ip, Alexander;  Ulissi, Zachary;  Sargent, Edward H.
收藏  |  浏览/下载:15/0  |  提交时间:2020/07/03

The biosynthetic pathway that produces the secondary bile acids DCA and LCA in human gut microbes has been fully characterized, engineered into another bacterial host, and used to confer DCA production in germ-free mice-an important proof-of-principle for the engineering of gut microbial pathways.


The gut microbiota synthesize hundreds of molecules, many of which influence host physiology. Among the most abundant metabolites are the secondary bile acids deoxycholic acid (DCA) and lithocholic acid (LCA), which accumulate at concentrations of around 500 mu M and are known to block the growth ofClostridium difficile(1), promote hepatocellular carcinoma(2)and modulate host metabolism via the G-protein-coupled receptor TGR5 (ref.(3)). More broadly, DCA, LCA and their derivatives are major components of the recirculating pool of bile acids(4)  the size and composition of this pool are a target of therapies for primary biliary cholangitis and nonalcoholic steatohepatitis. Nonetheless, despite the clear impact of DCA and LCA on host physiology, an incomplete knowledge of their biosynthetic genes and a lack of genetic tools to enable modification of their native microbial producers limit our ability to modulate secondary bile acid levels in the host. Here we complete the pathway to DCA and LCA by assigning and characterizing enzymes for each of the steps in its reductive arm, revealing a strategy in which the A-B rings of the steroid core are transiently converted into an electron acceptor for two reductive steps carried out by Fe-S flavoenzymes. Using anaerobic in vitro reconstitution, we establish that a set of six enzymes is necessary and sufficient for the eight-step conversion of cholic acid to DCA. We then engineer the pathway intoClostridium sporogenes, conferring production of DCA and LCA on a nonproducing commensal and demonstrating that a microbiome-derived pathway can be expressed and controlled heterologously. These data establish a complete pathway to two central components of the bile acid pool.


  
The fate of carbon in a mature forest under carbon dioxide enrichment 期刊论文
NATURE, 2020, 580 (7802) : 227-+
作者:  Sun, P. Z.;  Yang, Q.;  Kuang, W. J.;  Stebunov, Y. V.;  Xiong, W. Q.;  Yu, J.;  Nair, R. R.;  Katsnelson, M. I.;  Yuan, S. J.;  Grigorieva, I. V.;  Lozada-Hidalgo, M.;  Wang, F. C.;  Geim, A. K.
收藏  |  浏览/下载:71/0  |  提交时间:2020/05/13

Carbon dioxide enrichment of a mature forest resulted in the emission of the excess carbon back into the atmosphere via enhanced ecosystem respiration, suggesting that mature forests may be limited in their capacity to mitigate climate change.


Atmospheric carbon dioxide enrichment (eCO(2)) can enhance plant carbon uptake and growth(1-5), thereby providing an important negative feedback to climate change by slowing the rate of increase of the atmospheric CO2 concentration(6). Although evidence gathered from young aggrading forests has generally indicated a strong CO2 fertilization effect on biomass growth(3-5), it is unclear whether mature forests respond to eCO(2) in a similar way. In mature trees and forest stands(7-10), photosynthetic uptake has been found to increase under eCO(2) without any apparent accompanying growth response, leaving the fate of additional carbon fixed under eCO(2) unclear(4,5,7-11). Here using data from the first ecosystem-scale Free-Air CO2 Enrichment (FACE) experiment in a mature forest, we constructed a comprehensive ecosystem carbon budget to track the fate of carbon as the forest responded to four years of eCO(2) exposure. We show that, although the eCO(2) treatment of +150 parts per million (+38 per cent) above ambient levels induced a 12 per cent (+247 grams of carbon per square metre per year) increase in carbon uptake through gross primary production, this additional carbon uptake did not lead to increased carbon sequestration at the ecosystem level. Instead, the majority of the extra carbon was emitted back into the atmosphere via several respiratory fluxes, with increased soil respiration alone accounting for half of the total uptake surplus. Our results call into question the predominant thinking that the capacity of forests to act as carbon sinks will be generally enhanced under eCO(2), and challenge the efficacy of climate mitigation strategies that rely on ubiquitous CO2 fertilization as a driver of increased carbon sinks in global forests.


  
A genomic and epigenomic atlas of prostate cancer in Asian populations 期刊论文
NATURE, 2020: 93-+
作者:  Perry, Rachel J.;  Zhang, Dongyan;  Guerra, Mateus T.;  Brill, Allison L.;  Goedeke, Leigh;  Nasiri, Ali R.;  Rabin-Court, Aviva;  Wang, Yongliang;  Peng, Liang;  Dufour, Sylvie;  Zhang, Ye;  Zhang, Xian-Man;  Butrico, Gina M.;  Toussaint, Keshia;  Nozaki, Yuichi;  Cline, Gary W.;  Petersen, Kitt Falk;  Nathanson, Michael H.;  Ehrlich, Barbara E.;  Shulman, Gerald I.
收藏  |  浏览/下载:35/0  |  提交时间:2020/07/03

Prostate cancer is the second most common cancer in men worldwide(1). Over the past decade, large-scale integrative genomics efforts have enhanced our understanding of this disease by characterizing its genetic and epigenetic landscape in thousands of patients(2,3). However, most tumours profiled in these studies were obtained from patients from Western populations. Here we produced and analysed whole-genome, whole-transcriptome and DNA methylation data for 208 pairs of tumour tissue samples and matched healthy control tissue from Chinese patients with primary prostate cancer. Systematic comparison with published data from 2,554 prostate tumours revealed that the genomic alteration signatures in Chinese patients were markedly distinct from those of Western cohorts: specifically, 41% of tumours contained mutations in FOXA1 and 18% each had deletions in ZNF292 and CHD1. Alterations of the genome and epigenome were correlated and were predictive of disease phenotype and progression. Coding and noncoding mutations, as well as epimutations, converged on pathways that are important for prostate cancer, providing insights into this devastating disease. These discoveries underscore the importance of including population context in constructing comprehensive genomic maps for disease.


Genomic, transcriptomic and DNA methylation data from tissue samples from 208 Chinese patients with prostate cancer define the landscape of alterations in this population, and comparison with data from Western cohorts suggests that the disease may stratify into different molecular subtypes.


  
Metabolites released from apoptotic cells act as tissue messengers 期刊论文
NATURE, 2020
作者:  Chica, Daniel G.;  He, Yihui;  McCall, Kyle M.;  Chung, Duck Young;  Pak, Rahmi O.;  Trimarchi, Giancarlo;  Liu, Zhifu;  De Lurgio, Patrick M.;  Wessels, Bruce W.;  Kanatzidis, Mercouri G.
收藏  |  浏览/下载:16/0  |  提交时间:2020/07/03

Caspase-dependent apoptosis accounts for approximately 90% of homeostatic cell turnover in the body(1), and regulates inflammation, cell proliferation, and tissue regeneration(2-4). How apoptotic cells mediate such diverse effects is not fully understood. Here we profiled the apoptotic metabolite secretome and determined its effects on the tissue neighbourhood. We show that apoptotic lymphocytes and macrophages release specific metabolites, while retaining their membrane integrity. A subset of these metabolites is also shared across different primary cells and cell lines after the induction of apoptosis by different stimuli. Mechanistically, the apoptotic metabolite secretome is not simply due to passive emptying of cellular contents and instead is a regulated process. Caspase-mediated opening of pannexin 1 channels at the plasma membrane facilitated the release of a select subset of metabolites. In addition, certain metabolic pathways continued to remain active during apoptosis, with the release of only select metabolites from a given pathway. Functionally, the apoptotic metabolite secretome induced specific gene programs in healthy neighbouring cells, including suppression of inflammation, cell proliferation, and wound healing. Furthermore, a cocktail of apoptotic metabolites reduced disease severity in mouse models of inflammatory arthritis and lung-graft rejection. These data advance the concept that apoptotic cells are not inert cells waiting for removal, but instead release metabolites as '  good-bye'  signals to actively modulate outcomes in tissues.


Apoptotic cells communicate with neighbouring cells by the regulated release of specific metabolites, and a cocktail of select apoptotic metabolites reduces disease severity in mouse models of inflammatory arthritis and lung transplant rejection.


  
Epigenetic therapy inhibits metastases by disrupting premetastatic niches 期刊论文
NATURE, 2020, 579 (7798) : 284-+
作者:  Mehta, Vedanta;  Pang, Kar-Lai;  Rozbesky, Daniel;  Nather, Katrin;  Keen, Adam;  Lachowski, Dariusz;  Kong, Youxin;  Karia, Dimple;  Ameismeier, Michael;  Huang, Jianhua;  Fang, Yun;  del Rio Hernandez, Armando;  Reader, John S.;  Jones, E. Yvonne;  Tzima, Ellie
收藏  |  浏览/下载:18/0  |  提交时间:2020/07/03

Cancer recurrence after surgery remains an unresolved clinical problem(1-3). Myeloid cells derived from bone marrow contribute to the formation of the premetastatic microenvironment, which is required for disseminating tumour cells to engraft distant sites(4-6). There are currently no effective interventions that prevent the formation of the premetastatic microenvironment(6,7). Here we show that, after surgical removal of primary lung, breast and oesophageal cancers, low-dose adjuvant epigenetic therapy disrupts the premetastatic microenvironment and inhibits both the formation and growth of lung metastases through its selective effect on myeloid-derived suppressor cells (MDSCs). In mouse models of pulmonary metastases, MDSCs are key factors in the formation of the premetastatic microenvironment after resection of primary tumours. Adjuvant epigenetic therapy that uses low-dose DNA methyltransferase and histone deacetylase inhibitors, 5-azacytidine and entinostat, disrupts the premetastatic niche by inhibiting the trafficking of MDSCs through the downregulation of CCR2 and CXCR2, and by promoting MDSC differentiation into a more-interstitial macrophage-like phenotype. A decreased accumulation of MDSCs in the premetastatic lung produces longer periods of disease-free survival and increased overall survival, compared with chemotherapy. Our data demonstrate that, even after removal of the primary tumour, MDSCs contribute to the development of premetastatic niches and settlement of residual tumour cells. A combination of low-dose adjuvant epigenetic modifiers that disrupts this premetastatic microenvironment and inhibits metastases may permit an adjuvant approach to cancer therapy.


  
Global ocean primary production trends in the modern ocean color satellite record (1998?2015) 期刊论文
ENVIRONMENTAL RESEARCH LETTERS, 2019, 14 (12)
作者:  Gregg, Watson W.;  Rousseaux, Cecile S.
收藏  |  浏览/下载:8/0  |  提交时间:2020/02/17
ocean  primary production  data assimilation  trends  
Electricity theft among residential consumers in Rawalpindi and Islamabad 期刊论文
ENERGY POLICY, 2018, 123: 147-154
作者:  Jamil, Faisal
收藏  |  浏览/下载:3/0  |  提交时间:2019/04/09
Electricity theft  Primary data  Pakistan  Employees  Consumers  Tariff rate  
Joint structural and physiological control on the interannual variation in productivity in a temperate grassland: A data-model comparison 期刊论文
GLOBAL CHANGE BIOLOGY, 2018, 24 (7) : 2965-2979
作者:  Hu, Zhongmin;  Shi, Hao;  Cheng, Kaili;  Wang, Ying-Ping;  Piao, Shilong;  Li, Yue;  Zhang, Li;  Xia, Jianyang;  Zhou, Lei;  Yuan, Wenping;  Running, Steve;  Li, Longhui;  Hao, Yanbin;  He, Nianpeng;  Yu, Qiang;  Yu, Guirui
收藏  |  浏览/下载:10/0  |  提交时间:2019/04/09
data-model comparison  ecosystem models  grassland  gross primary productivity  interannual variability