全文获取类型
收费全文 | 6133篇 |
免费 | 576篇 |
国内免费 | 2篇 |
出版年
2023年 | 45篇 |
2022年 | 99篇 |
2021年 | 214篇 |
2020年 | 107篇 |
2019年 | 165篇 |
2018年 | 201篇 |
2017年 | 154篇 |
2016年 | 236篇 |
2015年 | 419篇 |
2014年 | 372篇 |
2013年 | 411篇 |
2012年 | 553篇 |
2011年 | 510篇 |
2010年 | 305篇 |
2009年 | 227篇 |
2008年 | 354篇 |
2007年 | 349篇 |
2006年 | 312篇 |
2005年 | 282篇 |
2004年 | 238篇 |
2003年 | 237篇 |
2002年 | 206篇 |
2001年 | 48篇 |
2000年 | 46篇 |
1999年 | 61篇 |
1998年 | 60篇 |
1997年 | 31篇 |
1996年 | 24篇 |
1995年 | 19篇 |
1994年 | 18篇 |
1993年 | 18篇 |
1992年 | 17篇 |
1991年 | 24篇 |
1990年 | 34篇 |
1989年 | 11篇 |
1988年 | 11篇 |
1987年 | 14篇 |
1986年 | 23篇 |
1985年 | 16篇 |
1984年 | 15篇 |
1983年 | 12篇 |
1982年 | 10篇 |
1981年 | 10篇 |
1980年 | 9篇 |
1979年 | 18篇 |
1978年 | 9篇 |
1973年 | 9篇 |
1968年 | 11篇 |
1966年 | 8篇 |
1962年 | 7篇 |
排序方式: 共有6711条查询结果,搜索用时 15 毫秒
91.
Phosphorylated p40PHOX as a negative regulator of NADPH oxidase 总被引:5,自引:0,他引:5
Lopes LR Dagher MC Gutierrez A Young B Bouin AP Fuchs A Babior BM 《Biochemistry》2004,43(12):3723-3730
The leukocyte NADPH oxidase catalyzes the production of O(2)(-) from oxygen at the expense of NADPH. Activation of the enzyme requires interaction of the cytosolic factors p47(PHOX), p67(PHOX), and Rac2 with the membrane-associated cytochrome b(558). Activation of the oxidase in a semirecombinant cell-free system in the absence of an amphiphilic activator can be achieved by phosphorylation of the cytosolic factor p47(PHOX) by protein kinase C. Another cytosolic factor, p40(PHOX), was recently shown to be phosphorylated on serine and threonine residues upon activation of NADPH oxidase, but both stimulatory and inhibitory roles were reported. In the present study, we demonstrate that the addition of phosphorylated p40(PHOX) to the cell-free system inhibits NADPH oxidase activated by protein kinase C-phosphorylated p47(PHOX), an effect not observed with the unphosphorylated p40(PHOX). Moreover phosphorylated p40(PHOX) inhibits the oxidase if added before or after full activation of the enzyme. Direct mutagenesis of protein kinase C consensus sites enables us to conclude that phosphorylation of threonine 154 is required for the inhibitory effect of p40(PHOX) to occur. Although the phosphorylated mutants and nonphosphorylated mutants are still able to interact with both p47(PHOX) and p67(PHOX) in pull-down assays, their proteolysis pattern upon thrombin treatment suggests a difference in conformation between the phosphorylated and nonphosphorylated mutants. We postulate that phosphorylation of p40(PHOX) on threonine 154 leads to an inhibitory conformation that shifts the balance toward an inhibitory role and blocks oxidase activation. 相似文献
92.
Nico Melzer Sven G. Meuth Delany Torres-Salazar Stefan Bittner Alla L. Zozulya Christian Weidenfeller Alexandra Kotsiari Martin Stangel Christoph Fahlke Heinz Wiendl 《PloS one》2008,3(9)
In multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE), impairment of glial “Excitatory Amino Acid Transporters” (EAATs) together with an excess glutamate-release by invading immune cells causes excitotoxic damage of the central nervous system (CNS). In order to identify pathways to dampen excitotoxic inflammatory CNS damage, we assessed the effects of a β-lactam antibiotic, ceftriaxone, reported to enhance expression of glial EAAT2, in “Myelin Oligodendrocyte Glycoprotein” (MOG)-induced EAE. Ceftriaxone profoundly ameliorated the clinical course of murine MOG-induced EAE both under preventive and therapeutic regimens. However, ceftriaxone had impact neither on EAAT2 protein expression levels in several brain areas, nor on the radioactive glutamate uptake capacity in a mixed primary glial cell-culture and the glutamate-induced uptake currents in a mammalian cell line mediated by EAAT2. Moreover, the clinical effect of ceftriaxone was preserved in the presence of the EAAT2-specific transport inhibitor, dihydrokainate, while dihydrokainate alone caused an aggravated EAE course. This demonstrates the need for sufficient glial glutamate uptake upon an excitotoxic autoimmune inflammatory challenge of the CNS and a molecular target of ceftriaxone other than the glutamate transporter. Ceftriaxone treatment indirectly hampered T cell proliferation and proinflammatory INFγ and IL17 secretion through modulation of myelin-antigen presentation by antigen-presenting cells (APCs) e.g. dendritic cells (DCs) and reduced T cell migration into the CNS in vivo. Taken together, we demonstrate, that a β-lactam antibiotic attenuates disease course and severity in a model of autoimmune CNS inflammation. The mechanisms are reduction of T cell activation by modulation of cellular antigen-presentation and impairment of antigen-specific T cell migration into the CNS rather than or modulation of central glutamate homeostasis. 相似文献
93.
Simon Schafferer Rimpi Khurana Violetta Refolo Serena Venezia Edith Sturm Paolo Piatti Clara Hechenberger Hubert Hackl Roman Kessler Michaela Willi Ronald Gstir Anne Krogsdam Alexandra Lusser Werner Poewe Gregor K. Wenning Alexander Hüttenhofer Nadia Stefanova 《PloS one》2016,11(3)
Multiple system atrophy (MSA) is a fatal rapidly progressive α-synucleinopathy, characterized by α-synuclein accumulation in oligodendrocytes. It is accepted that the pathological α-synuclein accumulation in the brain of MSA patients plays a leading role in the disease process, but little is known about the events in the early stages of the disease. In this study we aimed to define potential roles of the miRNA-mRNA regulatory network in the early pre-motor stages of the disease, i.e., downstream of α-synuclein accumulation in oligodendroglia, as assessed in a transgenic mouse model of MSA. We investigated the expression patterns of miRNAs and their mRNA targets in substantia nigra (SN) and striatum, two brain regions that undergo neurodegeneration at a later stage in the MSA model, by microarray and RNA-seq analysis, respectively. Analysis was performed at a time point when α-synuclein accumulation was already present in oligodendrocytes at neuropathological examination, but no neuronal loss nor deficits of motor function had yet occurred. Our data provide a first evidence for the leading role of gene dysregulation associated with deficits in immune and inflammatory responses in the very early, non-symptomatic disease stages of MSA. While dysfunctional homeostasis and oxidative stress were prominent in SN in the early stages of MSA, in striatum differential gene expression in the non-symptomatic phase was linked to oligodendroglial dysfunction, disturbed protein handling, lipid metabolism, transmembrane transport and altered cell death control, respectively. A large number of putative miRNA-mRNAs interaction partners were identified in relation to the control of these processes in the MSA model. Our results support the role of early changes in the miRNA-mRNA regulatory network in the pathogenesis of MSA preceding the clinical onset of the disease. The findings thus contribute to understanding the disease process and are likely to pave the way towards identifying disease biomarkers for early diagnosis of MSA. 相似文献
94.
95.
Larry M. Palato Shannon Pilcher Alissa Oakes Arleen Lamba Jaris Torres Litza I. Ledesma Monjaraz Crystabel Munoz Edward Njoo Dillon J. Rinauro Kate Alexandra Menefee Angela Tun Betssy L. Jauregui Sarah Shapiro Olivia H. Nossiff Eileen Olivares Kevin Chang Viviane Nguyen Luiza A. Nogaj David A. Moffet 《Journal of peptide science》2019,25(8)
The aggregation of the 37‐amino acid polypeptide human islet amyloid polypeptide (hIAPP), as either insoluble amyloid or as small oligomers, appears to play a direct role in the death of human pancreatic β‐islet cells in type 2 diabetes. hIAPP is considered to be one of the most amyloidogenic proteins known. The quick aggregation of hIAPP leads to the formation of toxic species, such as oligomers and fibers, that damage mammalian cells (both human and rat pancreatic cells). Whether this toxicity is necessary for the progression of type 2 diabetes or merely a side effect of the disease remains unclear. If hIAPP aggregation into toxic amyloid is on‐path for developing type 2 diabetes in humans, islet amyloid polypeptide (IAPP) aggregation would likely need to play a similar role within other organisms known to develop the disease. In this work, we compared the aggregation potential and cellular toxicity of full‐length IAPP from several diabetic and nondiabetic organisms whose aggregation propensities had not yet been determined for full‐length IAPP. 相似文献
96.
97.
Nada M. Abdel-Wahab Harwoko Harwoko Werner E.G. Müller Alexandra Hamacher Matthias U. Kassack Mostafa A. Fouad Mohamed S. Kamel Wenhan Lin Weaam Ebrahim Zhen Liu Peter Proksch 《Bioorganic & medicinal chemistry》2019,27(17):3954-3959
Three new cyclic heptapeptides (1–3) together with three known compounds (4–6) were isolated from a solid rice culture of the soil-derived fungus Clonostachys rosea. Fermentation of the fungus on white beans instead of rice afforded a new γ-lactam (7) and a known γ-lactone (8) that were not detected in the former extracts. The structures of the new compounds were elucidated on the basis of 1D and 2D NMR spectra as well as by HRESIMS data. Compounds 1 and 4 exhibited significant cytotoxicity against the L5178Y mouse lymphoma cell line with IC50 values of 4.1 and 0.1 µM, respectively. Compound 4 also displayed cytotoxicity against the A2780 human ovarian cancer cell line with an IC50 value of 3.5 µM. The preliminary structure-activity relationships are discussed. 相似文献
98.
99.
100.
Gerhardt H Golding M Fruttiger M Ruhrberg C Lundkvist A Abramsson A Jeltsch M Mitchell C Alitalo K Shima D Betsholtz C 《The Journal of cell biology》2003,161(6):1163-1177
Vascular endothelial growth factor (VEGF-A) is a major regulator of blood vessel formation and function. It controls several processes in endothelial cells, such as proliferation, survival, and migration, but it is not known how these are coordinately regulated to result in more complex morphogenetic events, such as tubular sprouting, fusion, and network formation. We show here that VEGF-A controls angiogenic sprouting in the early postnatal retina by guiding filopodial extension from specialized endothelial cells situated at the tips of the vascular sprouts. The tip cells respond to VEGF-A only by guided migration; the proliferative response to VEGF-A occurs in the sprout stalks. These two cellular responses are both mediated by agonistic activity of VEGF-A on VEGF receptor 2. Whereas tip cell migration depends on a gradient of VEGF-A, proliferation is regulated by its concentration. Thus, vessel patterning during retinal angiogenesis depends on the balance between two different qualities of the extracellular VEGF-A distribution, which regulate distinct cellular responses in defined populations of endothelial cells. 相似文献