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131.
Necroptosis and ferroptosis are alternative cell death pathways that operate in acute kidney failure
Tammo Müller Christin Dewitz Jessica Schmitz Anna Sophia Schröder Jan Hinrich Bräsen Brent R. Stockwell James M. Murphy Ulrich Kunzendorf Stefan Krautwald 《Cellular and molecular life sciences : CMLS》2017,74(19):3631-3645
Ferroptosis is a recently recognized caspase-independent form of regulated cell death that is characterized by the accumulation of lethal lipid ROS produced through iron-dependent lipid peroxidation. Considering that regulation of fatty acid metabolism is responsible for the membrane-resident pool of oxidizable fatty acids that undergo lipid peroxidation in ferroptotic processes, we examined the contribution of the key fatty acid metabolism enzyme, acyl-CoA synthetase long-chain family member 4 (ACSL4), in regulating ferroptosis. By using CRISPR/Cas9 technology, we found that knockout of Acsl4 in ferroptosis-sensitive murine and human cells conferred protection from erastin- and RSL3-induced cell death. In the same cell types, deletion of mixed lineage kinase domain-like (Mlkl) blocked susceptibility to necroptosis, as expected. Surprisingly, these studies also revealed ferroptosis and necroptosis are alternative, in that resistance to one pathway sensitized cells to death via the other pathway. These data suggest a mechanism by which one regulated necrosis pathway compensates for another when either ferroptosis or necroptosis is compromised. We verified the synergistic contributions of ferroptosis and necroptosis to tissue damage during acute organ failure in vivo. Interestingly, in the course of pathophysiological acute ischemic kidney injury, ACSL4 was initially upregulated and its expression level correlated with the severity of tissue damage. Together, our findings reveal ACSL4 to be a reliable biomarker of the emerging cell death modality of ferroptosis, which may also serve as a novel therapeutic target in preventing pathological cell death processes. 相似文献
132.
Frédéric?Delolme Cyril?Anastasi Lindsay?B.?Alcaraz Valentin?Mendoza Sandrine?Vadon-Le Goff Maya?Talantikite Robin?Capomaccio Jimmy?Mevaere La?titia?Fortin Dominique?Mazzocut Odile?Damour Isabelle?Zanella-Cléon David?J.?S.?Hulmes Christopher?M.?Overall Ulrich?Valcourt Fernando?Lopez-Casillas Catherine?MoaliEmail author 《Cellular and molecular life sciences : CMLS》2015,72(5):1009-1027
The metalloproteinase BMP-1 (bone morphogenetic protein-1) plays a major role in the control of extracellular matrix (ECM) assembly and growth factor activation. Most of the growth factors activated by BMP-1 are members of the TGF-β superfamily known to regulate multiple biological processes including embryonic development, wound healing, inflammation and tumor progression. In this study, we used an iTRAQ (isobaric tags for relative and absolute quantification)-based quantitative proteomic approach to reveal the release of proteolytic fragments from the cell surface or the ECM by BMP-1. Thirty-eight extracellular proteins were found in significantly higher or lower amounts in the conditioned medium of HT1080 cells overexpressing BMP-1 and thus, could be considered as candidate substrates. Strikingly, three of these new candidates (betaglycan, CD109 and neuropilin-1) were TGF-β co-receptors, also acting as antagonists when released from the cell surface, and were chosen for further substrate validation. Betaglycan and CD109 proved to be directly cleaved by BMP-1 and the corresponding cleavage sites were extensively characterized using a new mass spectrometry approach. Furthermore, we could show that the ability of betaglycan and CD109 to interact with TGF-β was altered after cleavage by BMP-1, leading to increased and prolonged SMAD2 phosphorylation in BMP-1-overexpressing cells. Betaglycan processing was also observed in primary corneal keratocytes, indicating a general and novel mechanism by which BMP-1 directly affects signaling by controlling TGF-β co-receptor activity. The proteomic data have been submitted to ProteomeXchange with the identifier PXD000786 and doi: 10.6019/PXD000786. 相似文献
133.
Nucleotides are of crucial importance as carriers of energy in all organisms. However, the concept that in addition to their
intracellular roles, nucleotides act as extracellular ligands specifically on receptors of the plasma membrane took longer
to be accepted. Purinergic signaling exerted by purines and pyrimidines, principally ATP and adenosine, occurs throughout
embryologic development in a wide variety of organisms, including amphibians, birds, and mammals. Cellular signaling, mediated
by ATP, is present in development at very early stages, e.g., gastrulation of Xenopus and germ layer definition of chick embryo cells. Purinergic receptor expression and functions have been studied in the development
of many organs, including the heart, eye, skeletal muscle and the nervous system. In vitro studies with stem cells revealed
that purinergic receptors are involved in the processes of proliferation, differentiation, and phenotype determination of
differentiated cells. Thus, nucleotides are able to induce various intracellular signaling pathways via crosstalk with other
bioactive molecules acting on growth factor and neurotransmitter receptors. Since normal development is disturbed by dysfunction
of purinergic signaling in animal models, further studies are needed to elucidate the functions of purinoceptor subtypes in
developmental processes. 相似文献
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136.
Zusammenfassung Zur vollständigen Ausschaltung des Sauerstoff-Effektes bei der Bestrahlung vonDrosophila-Embryonen genügt eine 15 Sekunden dauernde Vorbehandlung mit Stickstoff. 相似文献
137.
目的:合成1-苯甲基-4-[(5,6-二甲氧基-1-吲满酮)-2-甲基]甲基哌啶盐酸盐(Ⅰ),并对其合成工艺进行优化.方法:以5,6-二甲氧基-1-吲满酮、1-苯甲基-4-哌啶-甲醛为起始原料,经Adole缩合、还原、成盐等步骤制备Ⅰ.结果:总收率达60%以上,合成产物经熔点和红外光谱确认.结论:此合成工艺简便,易于工业化生产. 相似文献
138.
Ulrich Hoyer 《Archive for History of Exact Sciences》1978,19(4):371-381
Ohne Zusammenfassung
Vorgelegt von
S. Flügge 相似文献
139.
Ohne Zusammenfassung 相似文献
140.
Ohne Zusammenfassung
Vorgelegt von
L. Rosenfeld 相似文献