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Zizhen Yao Cindy T.J. van Velthoven Thuc Nghi Nguyen Jeff Goldy Adriana E. Sedeno-Cortes Fahimeh Baftizadeh Darren Bertagnolli Tamara Casper Megan Chiang Kirsten Crichton Song-Lin Ding Olivia Fong Emma Garren Alexandra Glandon Nathan W. Gouwens James Gray Lucas T. Graybuck Michael J. Hawrylycz Hongkui Zeng 《Cell》2021,184(12):3222-3241.e26
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Marina Mikhaylova Julia Bär Bas van Bommel Philipp Schätzle PingAn YuanXiang Rajeev Raman Johannes Hradsky Anja Konietzny Egor Y. Loktionov Pasham Parameshwar Reddy Jeffrey Lopez-Rojas Christina Spilker Oliver Kobler Syed Ahsan Raza Oliver Stork Casper C. Hoogenraad Michael R. Kreutz 《Neuron》2018,97(5):1110-1125.e14
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Michael Dumbacher Tom Van Dooren Katrien Princen Koen De Witte Mélissa Farinelli Sam Lievens Jan Tavernier Wim Dehaen Stefaan Wera Joris Winderickx Sara Allasia Amuri Kilonda Stéphane Spieser Arnaud Marchand Patrick Chaltin Casper C. Hoogenraad Gerard Griffioen 《Molecular neurodegeneration》2018,13(1):50
Background
Neuronal Ca2+ dyshomeostasis and hyperactivity play a central role in Alzheimer’s disease pathology and progression. Amyloid-beta together with non-genetic risk-factors of Alzheimer’s disease contributes to increased Ca2+ influx and aberrant neuronal activity, which accelerates neurodegeneration in a feed-forward fashion. As such, identifying new targets and drugs to modulate excessive Ca2+ signalling and neuronal hyperactivity, without overly suppressing them, has promising therapeutic potential.Methods
Here we show, using biochemical, electrophysiological, imaging, and behavioural tools, that pharmacological modulation of Rap1 signalling by inhibiting its interaction with Pde6δ normalises disease associated Ca2+ aberrations and neuronal activity, conferring neuroprotection in models of Alzheimer’s disease.Results
The newly identified inhibitors of the Rap1-Pde6δ interaction counteract AD phenotypes, by reconfiguring Rap1 signalling underlying synaptic efficacy, Ca2+ influx, and neuronal repolarisation, without adverse effects in-cellulo or in-vivo. Thus, modulation of Rap1 by Pde6δ accommodates key mechanisms underlying neuronal activity, and therefore represents a promising new drug target for early or late intervention in neurodegenerative disorders.Conclusion
Targeting the Pde6δ-Rap1 interaction has promising therapeutic potential for disorders characterised by neuronal hyperactivity, such as Alzheimer’s disease.78.
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Many Low Arctic tundra regions are currently undergoing a vegetation shift towards increasing growth and groundcover of tall deciduous shrubs due to recent climate warming. Vegetation change directly affects ecosystem carbon balance, but it can also affect soil biogeochemical cycling through physical and biological feedback mechanisms. Recent studies indicate that enhanced snow accumulation around relatively tall shrubs has negligible physical effect on litter decomposition rates. However, these investigations were no more than 3 years, and therefore may be insufficient to detect differences in inherently slow biogeochemical processes. Here, we report a 5-year study near Daring Lake, Canada, comparing Betula neoalaskana foliar litter decay rates within unmanipulated and snowfenced low-stature birch (height: ~?0.3 m) plots to test the physical effect of experimentally deepened snow, and within tall birch (height: ~?0.8 m) plots to test the combined physical and biological effects, that is, deepened snow plus strong birch dominance. Having corrected for carbon gain by the colonizing decomposers, actual litter carbon loss increased by approximately 25% in the tall birch relative to both low birch sites. Decay of lignin-like acid unhydrolizable litter residues also accelerated in the tall birch site, and a similar but lower magnitude response in the snowfenced low birch site indicated that physical effects of deepened snow were at least partially responsible. In contrast, deepened snow alone did not affect litter carbon loss. Our findings suggest that a combination of greater litter inputs, altered soil microbial community, enhanced soil nutrient pools, and warmer winter soils together promote relatively fast decomposition of recalcitrant litter carbon in tall birch shrub environments. 相似文献
80.
Effects of increased temperature on plant communities depend on landscape location and precipitation
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Jane Cowles Bazartseren Boldgiv Pierre Liancourt Peter S. Petraitis Brenda B. Casper 《Ecology and evolution》2018,8(11):5267-5278
Global climate change is affecting and will continue to affect ecosystems worldwide. Specifically, temperature and precipitation are both expected to shift globally, and their separate and interactive effects will likely affect ecosystems differentially depending on current temperature, precipitation regimes, and other biotic and environmental factors. It is not currently understood how the effects of increasing temperature on plant communities may depend on either precipitation or where communities lie on soil moisture gradients. Such knowledge would play a crucial role in increasing our predictive ability for future effects of climate change in different systems. To this end, we conducted a multi‐factor global change experiment at two locations, differing in temperature, moisture, aspect, and plant community composition, on the same slope in the northern Mongolian steppe. The natural differences in temperature and moisture between locations served as a point of comparison for the experimental manipulations of temperature and precipitation. We conducted two separate experiments, one examining the effect of climate manipulation via open‐top chambers (OTCs) across the two different slope locations, the other a factorial OTC by watering experiment at one of the two locations. By combining these experiments, we were able to assess how OTCs impact plant productivity and diversity across a natural and manipulated range of soil moisture. We found that warming effects were context dependent, with the greatest negative impacts of warming on diversity in the warmer, drier upper slope location and in the unwatered plots. Our study is an important step in understanding how global change will affect ecosystems across multiple scales and locations. 相似文献