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A heated response to danger 期刊论文
NATURE, 2020, 580 (7802)
作者:  Perry, Keston
收藏  |  浏览/下载:19/0  |  提交时间:2020/07/03

Psychological stress can trigger physiological responses, including an increase in body temperature. A neural circuit that underlies this stress-induced heat response has been identified.


  
A lower X-gate in TASK channels traps inhibitors within the vestibule 期刊论文
NATURE, 2020
作者:  Chen, Tao;  Nomura, Kinya;  Wang, Xiaolin;  Sohrabi, Reza;  Xu, Jin;  Yao, Lingya;  Paasch, Bradley C.;  Ma, Li;  Kremer, James;  Cheng, Yuti;  Zhang, Li;  Wang, Nian;  Wang, Ertao;  Xin, Xiu-Fang;  He, Sheng Yang
收藏  |  浏览/下载:64/0  |  提交时间:2020/07/03

TWIK-related acid-sensitive potassium (TASK) channels-members of the two pore domain potassium (K-2P) channel family-are found in neurons(1), cardiomyocytes(2-4) and vascular smooth muscle cells(5), where they are involved in the regulation of heart rate(6), pulmonary artery tone(5,7), sleep/wake cycles(8) and responses to volatile anaesthetics(8-11). K-2P channels regulate the resting membrane potential, providing background K+ currents controlled by numerous physiological stimuli(12-15). Unlike other K-2P channels, TASK channels are able to bind inhibitors with high affinity, exceptional selectivity and very slow compound washout rates. As such, these channels are attractive drug targets, and TASK-1 inhibitors are currently in clinical trials for obstructive sleep apnoea and atrial fibrillation(16). In general, potassium channels have an intramembrane vestibule with a selectivity filter situated above and a gate with four parallel helices located below  however, the K-2P channels studied so far all lack a lower gate. Here we present the X-ray crystal structure of TASK-1, and show that it contains a lower gate-which we designate as an '  X-gate'  -created by interaction of the two crossed C-terminal M4 transmembrane helices at the vestibule entrance. This structure is formed by six residues ((VLRFMT248)-V-243) that are essential for responses to volatile anaesthetics(10), neurotransmitters(13) and G-protein-coupled receptors(13). Mutations within the X-gate and the surrounding regions markedly affect both the channel-open probability and the activation of the channel by anaesthetics. Structures of TASK-1 bound to two high-affinity inhibitors show that both compounds bind below the selectivity filter and are trapped in the vestibule by the X-gate, which explains their exceptionally low washout rates. The presence of the X-gate in TASK channels explains many aspects of their physiological and pharmacological behaviour, which will be beneficial for the future development and optimization of TASK modulators for the treatment of heart, lung and sleep disorders.


The X-ray crystal structure of the potassium channel TASK-1 reveals the presence of an X-gate, which traps small-molecule inhibitors in the intramembrane vestibule and explains their low washout rates from the channel.


  
Feeding-dependent VIP neuron-ILC3 circuit regulates the intestinal barrier 期刊论文
NATURE, 2020, 579 (7800) : 575-+
作者:  Bhaduri, Aparna;  Andrews, Madeline G.;  Mancia Leon, Walter;  Jung, Diane;  Shin, David;  Allen, Denise;  Jung, Dana;  Schmunk, Galina;  Haeussler, Maximilian;  Salma, Jahan;  Pollen, Alex A.;  Nowakowski, Tomasz J.;  Kriegstein, Arnold R.
收藏  |  浏览/下载:55/0  |  提交时间:2020/07/03

The intestinal mucosa serves both as a conduit for the uptake of food-derived nutrients and microbiome-derived metabolites, and as a barrier that prevents tissue invasion by microorganisms and tempers inflammatory responses to the myriad contents of the lumen. How the intestine coordinates physiological and immune responses to food consumption to optimize nutrient uptake while maintaining barrier functions remains unclear. Here we show in mice how a gut neuronal signal triggered by food intake is integrated with intestinal antimicrobial and metabolic responses that are controlled by type-3 innate lymphoid cells (ILC3)(1-3). Food consumption rapidly activates a population of enteric neurons that express vasoactive intestinal peptide (VIP)(4). Projections of VIP-producing neurons (VIPergic neurons) in the lamina propria are in close proximity to clusters of ILC3 that selectively express VIP receptor type 2 (VIPR2  also known as VPAC2). Production of interleukin (IL)-22 by ILC3, which is upregulated by the presence of commensal microorganisms such as segmented filamentous bacteria(5-7), is inhibited upon engagement of VIPR2. As a consequence, levels of antimicrobial peptide derived from epithelial cells are reduced but the expression of lipid-binding proteins and transporters is increased(8). During food consumption, the activation of VIPergic neurons thus enhances the growth of segmented filamentous bacteria associated with the epithelium, and increases lipid absorption. Our results reveal a feeding- and circadian-regulated dynamic neuroimmune circuit in the intestine that promotes a trade-off between innate immune protection mediated by IL-22 and the efficiency of nutrient absorption. Modulation of this pathway may therefore be effective for enhancing resistance to enteropathogens(2,3,9) and for the treatment of metabolic diseases.


Feeding controls a neuroimmune circuit comprising VIP-producing neurons and type-3 innate lymphoid cells that helps to regulate the efficiency of nutrient uptake and IL-22-mediated immune protection in the intestine.


  
Groundwater drawdown drives ecophysiological adjustments of woody vegetation in a semi-arid coastal ecosystem 期刊论文
GLOBAL CHANGE BIOLOGY, 2018, 24 (10) : 4894-4908
作者:  Antunes, Cristina;  Chozas, Sergio;  West, Jason;  Zunzunegui, Maria;  Diaz Barradas, Maria Cruz;  Vieira, Simone;  Maguas, Cristina
收藏  |  浏览/下载:19/0  |  提交时间:2019/04/09
coastal dune ecosystem  groundwater table depth  photosynthetic activity  physiological responses  plant functional types  plant water status  water table lowering  water-uptake depth  
Role of population genetics in guiding ecological responses to climate 期刊论文
GLOBAL CHANGE BIOLOGY, 2018, 24 (2) : 858-868
作者:  Rehfeldt, Gerald E.;  Leites, Laura P.;  Joyce, Dennis G.;  Weiskittel, Aaron R.
收藏  |  浏览/下载:12/0  |  提交时间:2019/04/09
climate change responses  ecological genetics  ecological optimum  genetic differentiation  genotype-environment interactions  growth potential-cold hardiness tradeoff  physiological optimum