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排序方式: 共有343条查询结果,搜索用时 15 毫秒
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Frezza C Zheng L Folger O Rajagopalan KN MacKenzie ED Jerby L Micaroni M Chaneton B Adam J Hedley A Kalna G Tomlinson IP Pollard PJ Watson DG Deberardinis RJ Shlomi T Ruppin E Gottlieb E 《Nature》2011,477(7363):225-228
Fumarate hydratase (FH) is an enzyme of the tricarboxylic acid cycle (TCA cycle) that catalyses the hydration of fumarate into malate. Germline mutations of FH are responsible for hereditary leiomyomatosis and renal-cell cancer (HLRCC). It has previously been demonstrated that the absence of FH leads to the accumulation of fumarate, which activates hypoxia-inducible factors (HIFs) at normal oxygen tensions. However, so far no mechanism that explains the ability of cells to survive without a functional TCA cycle has been provided. Here we use newly characterized genetically modified kidney mouse cells in which Fh1 has been deleted, and apply a newly developed computer model of the metabolism of these cells to predict and experimentally validate a linear metabolic pathway beginning with glutamine uptake and ending with bilirubin excretion from Fh1-deficient cells. This pathway, which involves the biosynthesis and degradation of haem, enables Fh1-deficient cells to use the accumulated TCA cycle metabolites and permits partial mitochondrial NADH production. We predicted and confirmed that targeting this pathway would render Fh1-deficient cells non-viable, while sparing wild-type Fh1-containing cells. This work goes beyond identifying a metabolic pathway that is induced in Fh1-deficient cells to demonstrate that inhibition of haem oxygenation is synthetically lethal when combined with Fh1 deficiency, providing a new potential target for treating HLRCC patients. 相似文献
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Genome sequencing reveals insights into physiology and longevity of the naked mole rat 总被引:1,自引:0,他引:1
Kim EB Fang X Fushan AA Huang Z Lobanov AV Han L Marino SM Sun X Turanov AA Yang P Yim SH Zhao X Kasaikina MV Stoletzki N Peng C Polak P Xiong Z Kiezun A Zhu Y Chen Y Kryukov GV Zhang Q Peshkin L Yang L Bronson RT Buffenstein R Wang B Han C Li Q Chen L Zhao W Sunyaev SR Park TJ Zhang G Wang J Gladyshev VN 《Nature》2011,479(7372):223-227
225.
Nanofabrication strategies are becoming increasingly expensive and equipment-intensive, and consequently less accessible to researchers. As an alternative, scanning probe lithography has become a popular means of preparing nanoscale structures, in part owing to its relatively low cost and high resolution, and a registration accuracy that exceeds most existing technologies. However, increasing the throughput of cantilever-based scanning probe systems while maintaining their resolution and registration advantages has from the outset been a significant challenge. Even with impressive recent advances in cantilever array design, such arrays tend to be highly specialized for a given application, expensive, and often difficult to implement. It is therefore difficult to imagine commercially viable production methods based on scanning probe systems that rely on conventional cantilevers. Here we describe a low-cost and scalable cantilever-free tip-based nanopatterning method that uses an array of hard silicon tips mounted onto an elastomeric backing. This method-which we term hard-tip, soft-spring lithography-overcomes the throughput problems of cantilever-based scanning probe systems and the resolution limits imposed by the use of elastomeric stamps and tips: it is capable of delivering materials or energy to a surface to create arbitrary patterns of features with sub-50-nm resolution over centimetre-scale areas. We argue that hard-tip, soft-spring lithography is a versatile nanolithography strategy that should be widely adopted by academic and industrial researchers for rapid prototyping applications. 相似文献
226.
Vinod Sundaramoorthy Adam K. Walker Justin Yerbury Kai Ying Soo Manal A. Farg Vy Hoang Rafaa Zeineddine Damian Spencer Julie D. Atkin 《Cellular and molecular life sciences : CMLS》2013,70(21):4181-4195
Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing neurodegenerative disorder and the majority of ALS is sporadic, where misfolding and aggregation of Cu/Zn-superoxide dismutase (SOD1) is a feature shared with familial mutant-SOD1 cases. ALS is characterized by progressive neurospatial spread of pathology among motor neurons, and recently the transfer of extracellular, aggregated mutant SOD1 between cells was demonstrated in culture. However, there is currently no evidence that uptake of SOD1 into cells initiates neurodegenerative pathways reminiscent of ALS pathology. Similarly, whilst dysfunction to the ER–Golgi compartments is increasingly implicated in the pathogenesis of both sporadic and familial ALS, it remains unclear whether misfolded, wildtype SOD1 triggers ER–Golgi dysfunction. In this study we show that both extracellular, native wildtype and mutant SOD1 are taken up by macropinocytosis into neuronal cells. Hence uptake does not depend on SOD1 mutation or misfolding. We also demonstrate that purified mutant SOD1 added exogenously to neuronal cells inhibits protein transport between the ER–Golgi apparatus, leading to Golgi fragmentation, induction of ER stress and apoptotic cell death. Furthermore, we show that extracellular, aggregated, wildtype SOD1 also induces ER–Golgi pathology similar to mutant SOD1, leading to apoptotic cell death. Hence extracellular misfolded wildtype or mutant SOD1 induce dysfunction to ER–Golgi compartments characteristic of ALS in neuronal cells, implicating extracellular SOD1 in the spread of pathology among motor neurons in both sporadic and familial ALS. 相似文献
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Luo Sanzhong Zhang Baolian Xian Ming Adam JaÑczuk Xie Wenhua Cheng Jinpei Peng George Wang 《科学通报(英文版)》2001,46(20):1673-1680
Lanthanide triflates are stable in water. It is possible for lanthanides to undergo many organic reactions in environmentally
friendly solvents. This makes lanthanides very promising in the field of green chemistry. This review describes the recent
development of the lanthanidecatalyzed organic reactions in protic solvents. Those reactions include Diels-Alder, Aldol, Allylation,
acetalization, pericyclization, radical reactions as well as some newlydeveloped lanthnidesbased catalysts. 相似文献
230.
Megan Chircop Chandra S. Malladi Audrey T. Lian Scott L. Page Michael Zavortink Christopher P. Gordon Adam McCluskey Phillip J. Robinson 《Cellular and molecular life sciences : CMLS》2010,67(21):3725-3737
Successful completion of cytokinesis requires the spatio-temporal regulation of protein phosphorylation and the coordinated
activity of protein kinases and phosphatases. Many mitotic protein kinases are well characterized while mitotic phosphatases
are largely unknown. Here, we show that the Ca2+- and calmodulin-dependent phosphatase, calcineurin (CaN), is required for cytokinesis in mammalian cells, functioning specifically
at the abscission stage. CaN inhibitors induce multinucleation in HeLa cells and prolong the time cells spend connected via
an extended intracellular bridge. Upon Ca2+ influx during cytokinesis, CaN is activated, targeting a set of proteins for dephosphorylation, including dynamin II (dynII).
At the intracellular bridge, phospho-dynII and CaN are co-localized to dual flanking midbody rings (FMRs) that reside on either
side of the central midbody ring. CaN activity and disassembly of the FMRs coincide with abscission. Thus, CaN activity at
the midbody plays a key role in regulating the completion of cytokinesis in mammalian cells. 相似文献