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An acute immune response underlies the benefit of cardiac stem cell therapy 期刊论文
NATURE, 2020, 577 (7790) : 405-+
作者:  Schmacke, Niklas A.;  Hornung, Veit
收藏  |  浏览/下载:39/0  |  提交时间:2020/07/03

Clinical trials using adult stem cells to regenerate damaged heart tissue continue to this day(1,2), despite ongoing questions of efficacy and a lack of mechanistic understanding of the underlying biological effect(3). The rationale for these cell therapy trials is derived from animal studies that show a modest but reproducible improvement in cardiac function in models of cardiac ischaemic injury(4,5). Here we examine the mechanistic basis for cell therapy in mice after ischaemia-reperfusion injury, and find that-although heart function is enhanced-it is not associated with the production of new cardiomyocytes. Cell therapy improved heart function through an acute sterile immune response characterized by the temporal and regional induction of CCR2(+) and CX3CR1(+) macrophages. Intracardiac injection of two distinct types of adult stem cells, cells killed by freezing and thawing or a chemical inducer of the innate immune response all induced a similar regional accumulation of CCR2(+) and CX3CR1(+) macrophages, and provided functional rejuvenation to the heart after ischaemia-reperfusion injury. This selective macrophage response altered the activity of cardiac fibroblasts, reduced the extracellular matrix content in the border zone and enhanced the mechanical properties of the injured area. The functional benefit of cardiac cell therapy is thus due to an acute inflammatory-based wound-healing response that rejuvenates the infarcted area of the heart.


  
The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K 期刊论文
NATURE, 2020
作者:  Chen, Guorui;  Sharpe, Aaron L.;  Fox, Eli J.;  Zhang, Ya-Hui;  Wang, Shaoxin;  Jiang, Lili;  Lyu, Bosai;  Li, Hongyuan;  Watanabe, Kenji;  Taniguchi, Takashi;  Shi, Zhiwen;  Senthil, T.;  Goldhaber-Gordon, David;  Zhang, Yuanbo;  Wang, Feng
收藏  |  浏览/下载:67/0  |  提交时间:2020/07/03

The cyclin-dependent kinase inhibitor CR8 acts as a molecular glue compound by inducing the formation of a complex between CDK12-cyclin K and DDB1, which results in the ubiquitination and degradation of cyclin K.


Molecular glue compounds induce protein-protein interactions that, in the context of a ubiquitin ligase, lead to protein degradation(1). Unlike traditional enzyme inhibitors, these molecular glue degraders act substoichiometrically to catalyse the rapid depletion of previously inaccessible targets(2). They are clinically effective and highly sought-after, but have thus far only been discovered serendipitously. Here, through systematically mining databases for correlations between the cytotoxicity of 4,518 clinical and preclinical small molecules and the expression levels of E3 ligase components across hundreds of human cancer cell lines(3-5), we identify CR8-a cyclin-dependent kinase (CDK) inhibitor(6)-as a compound that acts as a molecular glue degrader. The CDK-bound form of CR8 has a solvent-exposed pyridyl moiety that induces the formation of a complex between CDK12-cyclin K and the CUL4 adaptor protein DDB1, bypassing the requirement for a substrate receptor and presenting cyclin K for ubiquitination and degradation. Our studies demonstrate that chemical alteration of surface-exposed moieties can confer gain-of-function glue properties to an inhibitor, and we propose this as a broader strategy through which target-binding molecules could be converted into molecular glues.


  
Spin current from sub-terahertz-generated antiferromagnetic magnons 期刊论文
NATURE, 2020, 578 (7793) : 70-+
作者:  Zemp, M.;  Huss, M.;  Thibert, E.;  Eckert, N.;  McNabb, R.;  Huber, J.;  Barandun, M.;  Machguth, H.;  Nussbaumer, S. U.;  Gartner-Roer, I.;  Thomson, L.;  Paul, F.;  Maussion, F.;  Kutuzov, S.;  Cogley, J. G.
收藏  |  浏览/下载:54/0  |  提交时间:2020/07/03

Pure spin currents are simultaneously generated and detected electrically through sub-terahertz magnons in the antiferromagnetic insulator Cr2O3, demonstrating the potential of magnon excitations in antiferromagnets for high-frequency spintronic devices.


Spin dynamics in antiferromagnets has much shorter timescales than in ferromagnets, offering attractive properties for potential applications in ultrafast devices(1-3). However, spin-current generation via antiferromagnetic resonance and simultaneous electrical detection by the inverse spin Hall effect in heavy metals have not yet been explicitly demonstrated(4-6). Here we report sub-terahertz spin pumping in heterostructures of a uniaxial antiferromagnetic Cr2O3 crystal and a heavy metal (Pt or Ta in its beta phase). At 0.240 terahertz, the antiferromagnetic resonance in Cr2O3 occurs at about 2.7 tesla, which excites only right-handed magnons. In the spin-canting state, another resonance occurs at 10.5 tesla from the precession of induced magnetic moments. Both resonances generate pure spin currents in the heterostructures, which are detected by the heavy metal as peaks or dips in the open-circuit voltage. The pure-spin-current nature of the electrically detected signals is unambiguously confirmed by the reversal of the voltage polarity observed under two conditions: when switching the detector metal from Pt to Ta, reversing the sign of the spin Hall angle(7-9), and when flipping the magnetic-field direction, reversing the magnon chirality(4,5). The temperature dependence of the electrical signals at both resonances suggests that the spin current contains both coherent and incoherent magnon contributions, which is further confirmed by measurements of the spin Seebeck effect and is well described by a phenomenological theory. These findings reveal the unique characteristics of magnon excitations in antiferromagnets and their distinctive roles in spin-charge conversion in the high-frequency regime.


  
Inconsistent Wind Speed Trends in Current Twentieth Century Reanalyses 期刊论文
JOURNAL OF GEOPHYSICAL RESEARCH-ATMOSPHERES, 2019, 124 (4) : 1931-1940
作者:  Wohland, Jan;  Omrani, Nour-Eddine;  Witthaut, Dirk;  Keenlyside, Noel S.
收藏  |  浏览/下载:21/0  |  提交时间:2019/04/09
wind  reanalysis  spurious trend  discrepancy  ERA20C  20CR  
The October 1891 Cartago (Costa Rica) floods from documentary sources and 20CR data 期刊论文
INTERNATIONAL JOURNAL OF CLIMATOLOGY, 2018, 38 (13) : 4830-4845
作者:  Amador, Jorge A.;  Anderson, Maria J.;  Calderon, Blanca;  Pribyl, Kathleen
收藏  |  浏览/下载:18/0  |  提交时间:2019/04/09
temporales  20CR data  Cartago floods  extreme events  historical climatology  societal impacts  
Skill of the two 20th century reanalyses in representing Antarctic near-surface air temperature 期刊论文
INTERNATIONAL JOURNAL OF CLIMATOLOGY, 2018, 38 (11) : 4225-4238
作者:  Zhang, Yulun;  Wang, Yetang;  Huai, Baojuan;  Ding, Minghu;  Sun, Weijun
收藏  |  浏览/下载:23/0  |  提交时间:2019/04/09
20CR and ERA-20CR  Antarctic ice sheet  near-surface air temperature  
On the ability of RCMs to capture the circulation pattern of Etesians 期刊论文
CLIMATE DYNAMICS, 2018, 51: 1687-1706
作者:  Dafka, Stella;  Toreti, Andrea;  Luterbacher, Juerg;  Zanis, Prodromos;  Tyrlis, Evangelos;  Xoplaki, Elena
收藏  |  浏览/下载:17/0  |  提交时间:2019/04/09
Etesians  Extreme wind  RCMs evaluation  Added value  20CR-v2c  ERA-20C  
Euro-Atlantic blocking events and their impact on surface air temperature and precipitation over the European region in the 20th century 期刊论文
CLIMATE RESEARCH, 2017, 71 (3)
作者:  Stankunavicius, Gintautas;  Basharin, Dmitry;  Skorupskas, Richardas;  Vivaldo, Gianna
收藏  |  浏览/下载:10/0  |  提交时间:2019/04/09
Euro-Atlantic Blocking  Twentieth Century Reanalysis  20CR  Temperature and precipitation  Europe  
Testing Novel CR-39 Detector Deployment System For Identification of Subsurface Fractures, Soda Springs, ID 科技报告
来源:US Department of Energy (DOE). 出版年: 2015
作者:  McLing, Travis;  Carpenter, Michael;  Brandon, William;  Zavala, Bernie
收藏  |  浏览/下载:12/0  |  提交时间:2019/04/05
CR-39 detector  deployment  fractures  Subsurface  system  
Corrective Action Decision Document/Closure Report for Corrective Action Unit 550: Smoky Contamination Area Nevada National Security Site, Nevada, Revision 0 科技报告
来源:US Department of Energy (DOE). 出版年: 2015
作者:  Matthews, Patrick K.
收藏  |  浏览/下载:8/0  |  提交时间:2019/04/05
CADD/CR  CAU 550  Smoky Site  Contamination Area