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Quantifying the role of internal variability in the temperature we expect to observe in the coming decades 期刊论文
ENVIRONMENTAL RESEARCH LETTERS, 2020, 15 (5)
作者:  Maher, Nicola;  Lehner, Flavio;  Marotzke, Jochem
收藏  |  浏览/下载:13/0  |  提交时间:2020/07/02
internal variability  SMILEs  large ensembles  short-term projections  mid-term projections  surface temperature  model differences  
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:32/0  |  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.


  
Olfactory receptor and circuit evolution promote host specialization 期刊论文
NATURE, 2020
作者:  Chen, Tse-An;  Chuu, Chih-Piao;  Tseng, Chien-Chih;  Wen, Chao-Kai;  Wong, H. -S. Philip;  Pan, Shuangyuan;  Li, Rongtan;  Chao, Tzu-Ang;  Chueh, Wei-Chen;  Zhang, Yanfeng;  Fu, Qiang;  Yakobson, Boris I.;  Chang, Wen-Hao;  Li, Lain-Jong
收藏  |  浏览/下载:35/0  |  提交时间:2020/07/03

The evolution of animal behaviour is poorly understood(1,2). Despite numerous correlations between interspecific divergence in behaviour and nervous system structure and function, demonstrations of the genetic basis of these behavioural differences remain rare(3-5). Here we develop a neurogenetic model, Drosophila sechellia, a species that displays marked differences in behaviour compared to its close cousin Drosophila melanogaster(6,7), which are linked to its extreme specialization on noni fruit (Morinda citrifolia)(8-16). Using calcium imaging, we identify olfactory pathways in D. sechellia that detect volatiles emitted by the noni host. Our mutational analysis indicates roles for different olfactory receptors in long- and short-range attraction to noni, and our cross-species allele-transfer experiments demonstrate that the tuning of one of these receptors is important for species-specific host-seeking. We identify the molecular determinants of this functional change, and characterize their evolutionary origin and behavioural importance. We perform circuit tracing in the D. sechellia brain, and find that receptor adaptations are accompanied by increased sensory pooling onto interneurons as well as species-specific central projection patterns. This work reveals an accumulation of molecular, physiological and anatomical traits that are linked to behavioural divergence between species, and defines a model for investigating speciation and the evolution of the nervous system.


A neurogenetic model, Drosophila sechellia-a relative of Drosophila melanogaster that has developed an extreme specialization for a single host plant-sheds light on the evolution of interspecific differences in behaviour.


  
CRISPR screens in cancer spheroids identify 3D growth-specific vulnerabilities 期刊论文
NATURE, 2020
作者:  Yang, Jianfeng;  Faccenda, Manuele
收藏  |  浏览/下载:28/0  |  提交时间:2020/07/03

Cancer genomics studies have identified thousands of putative cancer driver genes(1). Development of high-throughput and accurate models to define the functions of these genes is a major challenge. Here we devised a scalable cancer-spheroid model and performed genome-wide CRISPR screens in 2D monolayers and 3D lung-cancer spheroids. CRISPR phenotypes in 3D more accurately recapitulated those of in vivo tumours, and genes with differential sensitivities between 2D and 3D conditions were highly enriched for genes that are mutated in lung cancers. These analyses also revealed drivers that are essential for cancer growth in 3D and in vivo, but not in 2D. Notably, we found that carboxypeptidase D is responsible for removal of a C-terminal RKRR motif(2) from the alpha-chain of the insulin-like growth factor 1 receptor that is critical for receptor activity. Carboxypeptidase D expression correlates with patient outcomes in patients with lung cancer, and loss of carboxypeptidase D reduced tumour growth. Our results reveal key differences between 2D and 3D cancer models, and establish a generalizable strategy for performing CRISPR screens in spheroids to reveal cancer vulnerabilities.


CRISPR screens in a 3D spheroid cancer model system more accurately recapitulate cancer phenotypes than existing 2D models and were used to identify carboxypeptidase D, acting via the IGF1R, as a 3D-specific driver of cancer growth.


  
A 4D spatio-temporal approach to modelling land value uplift from rapid transit in high density and topographically-rich cities 期刊论文
LANDSCAPE AND URBAN PLANNING, 2019, 185: 68-82
作者:  Higgins, Christopher D.
收藏  |  浏览/下载:14/0  |  提交时间:2019/11/26
Rapid transit  Hedonic price model  Difference-in-differences  Pedestrian accessibility  Spatio-temporal econometrics  Land value capture