全文获取类型
收费全文 | 530篇 |
免费 | 49篇 |
出版年
2023年 | 3篇 |
2022年 | 14篇 |
2021年 | 11篇 |
2020年 | 15篇 |
2019年 | 9篇 |
2018年 | 16篇 |
2017年 | 12篇 |
2016年 | 17篇 |
2015年 | 33篇 |
2014年 | 22篇 |
2013年 | 31篇 |
2012年 | 45篇 |
2011年 | 49篇 |
2010年 | 37篇 |
2009年 | 19篇 |
2008年 | 29篇 |
2007年 | 36篇 |
2006年 | 30篇 |
2005年 | 34篇 |
2004年 | 17篇 |
2003年 | 14篇 |
2002年 | 20篇 |
2001年 | 5篇 |
1999年 | 4篇 |
1997年 | 3篇 |
1996年 | 3篇 |
1995年 | 3篇 |
1994年 | 3篇 |
1993年 | 2篇 |
1992年 | 2篇 |
1988年 | 3篇 |
1987年 | 2篇 |
1985年 | 2篇 |
1983年 | 2篇 |
1981年 | 1篇 |
1980年 | 1篇 |
1979年 | 5篇 |
1978年 | 2篇 |
1977年 | 4篇 |
1976年 | 1篇 |
1975年 | 3篇 |
1974年 | 1篇 |
1973年 | 2篇 |
1972年 | 1篇 |
1970年 | 1篇 |
1969年 | 1篇 |
1968年 | 1篇 |
1967年 | 1篇 |
1959年 | 2篇 |
1958年 | 1篇 |
排序方式: 共有579条查询结果,搜索用时 524 毫秒
531.
Prashant Sharma Bhavnesh Kumar Yash Gupta Neelja Singhal Vishwa Mohan Katoch Krishnamurthy Venkatesan Deepa Bisht 《Proteome science》2010,8(1):59
Background
Streptomycin (SM) is a broad spectrum antibiotic and is an important component of any anti-tuberculosis therapy regimen. Several mechanisms have been proposed to explain the emergence of resistance but still our knowledge is inadequate. Proteins form a very complex network and drugs are countered by their modification/efflux or over expression/modification of targets. As proteins manifest most of the biological processes, these are attractive targets for developing drugs, immunodiagnostics or therapeutics. The aim of present study was to analyze and compare the protein profile of whole cell extracts from Mycobacterium tuberculosis clinical isolates susceptible and resistant to SM. 相似文献532.
533.
Regulation of Renal Epithelial Tight Junctions by the von Hippel-Lindau Tumor Suppressor Gene Involves Occludin and Claudin 1 and Is Independent of E-Cadherin 下载免费PDF全文
Sarah K. Harten Deepa Shukla Ravi Barod Alexander Hergovich Maria S. Balda Karl Matter Miguel A. Esteban Patrick H. Maxwell 《Molecular biology of the cell》2009,20(3):1089-1101
Epithelial-to-mesenchymal transitions (EMT) are important in renal development, fibrosis, and cancer. Loss of function of the tumor suppressor VHL leads to many features of EMT, and it has been hypothesized that the pivotal mediator is down-regulation of the adherens junction (AJ) protein E-cadherin. Here we show that VHL loss-of-function also has striking effects on the expression of the tight junction (TJ) components occludin and claudin 1 in vitro in VHL-defective clear cell renal cell carcinoma (CCRCC) cells and in vivo in VHL-defective sporadic CCRCCs (compared with normal kidney). Occludin is also down-regulated in premalignant foci in kidneys from patients with germline VHL mutations, consistent with a contribution to CCRCC initiation. Reexpression of E-cadherin was sufficient to restore AJ but not TJ assembly, indicating that the TJ defect is independent of E-cadherin down-regulation. Additional experiments show that activation of hypoxia inducible factor (HIF) contributes to both TJ and AJ abnormalities, thus the VHL/HIF pathway contributes to multiple aspects of the EMT phenotype that are not interdependent. Despite the independent nature of the defects, we show that treatment with the histone deacetylase inhibitor sodium butyrate, which suppresses HIF activation, provides a method for reversing EMT in the context of VHL inactivation. 相似文献
534.
Vesna Gagic David Kleijn András Báldi Gergely Boros Helene Bracht Jørgensen Zoltán Elek Michael P. D. Garratt G. Arjen de Groot Katarina Hedlund Anikó Kovács‐Hostyánszki Lorenzo Marini Emily Martin Ines Pevere Simon G. Potts Sarah Redlich Deepa Senapathi Ingolf Steffan‐Dewenter Stanislaw Świtek Henrik G. Smith Viktória Takács Piotr Tryjanowski Wim H. van der Putten Stijn van Gils Riccardo Bommarco 《Ecology letters》2017,20(11):1427-1436
Simultaneously enhancing ecosystem services provided by biodiversity below and above ground is recommended to reduce dependence on chemical pesticides and mineral fertilisers in agriculture. However, consequences for crop yield have been poorly evaluated. Above ground, increased landscape complexity is assumed to enhance biological pest control, whereas below ground, soil organic carbon is a proxy for several yield‐supporting services. In a field experiment replicated in 114 fields across Europe, we found that fertilisation had the strongest positive effect on yield, but hindered simultaneous harnessing of below‐ and above‐ground ecosystem services. We furthermore show that enhancing natural enemies and pest control through increasing landscape complexity can prove disappointing in fields with low soil services or in intensively cropped regions. Thus, understanding ecological interdependences between land use, ecosystem services and yield is necessary to promote more environmentally friendly farming by identifying situations where ecosystem services are maximised and agrochemical inputs can be reduced. 相似文献
535.
c-Jun N-terminal kinase (JNK) contributes to metalloproteinase (MMP) gene expression and joint destruction in inflammatory
arthritis. It is phosphorylated by at least two upstream kinases, the mitogen-activated protein kinase kinases (MEK) MKK4
and MKK7, which are, in turn, phosphorylated by MEK kinases (MEKKs). However, the MEKKs that are most relevant to JNK activation
in synoviocytes have not been determined. These studies were designed to assess the hierarchy of upstream MEKKs, MEKK1, MEKK2,
MEKK3, and transforming growth factor-β activated kinase (TAK)1, in rheumatoid arthritis (RA). Using either small interfering
RNA (siRNA) knockdown or knockout fibroblast-like synoviocytes (FLSs), MEKK1, MEKK2, or MEKK3 deficiency (either alone or
in combination) had no effect on IL-1β-stimulated phospho-JNK (P-JNK) induction or MMP expression. However, TAK1 deficiency
significantly decreased P-JNK, P-MKK4 and P-MKK7 induction compared with scrambled control. TAK1 knockdown did not affect
p38 activation. Kinase assays showed that TAK1 siRNA significantly suppressed JNK kinase function. In addition, MKK4 and MKK7
kinase activity were significantly decreased in TAK1 deficient FLSs. Electrophoretic mobility shift assays demonstrated a
significant decrease in IL-1β induced AP-1 activation due to TAK1 knockdown. Quantitative PCR showed that TAK1 deficiency
significantly decreased IL-1β-induced MMP3 gene expression and IL-6 protein expression. These results show that TAK1 is a
critical pathway for IL-1β-induced activation of JNK and JNK-regulated gene expression in FLSs. In contrast to other cell
lineages, MEKK1, MEKK2, and MEKK3 did not contribute to JNK phosphorylation in FLSs. The data identify TAK1 as a pivotal upstream
kinase and potential therapeutic target to modulate synoviocyte activation in RA. 相似文献
536.
537.
Deepa Balasubramaniam Oliver Schroeder Anna M. Russell Jonathan R. Fitchett Aaron K. Austin Thomas P. Beyer Yan Q. Chen Jonathan W. Day Mariam Ehsani Aik Roy Heng Eugene Y. Zhen Julian Davies Wolfgang Glaesner Bryan E. Jones Robert W. Siegel Yue-Wei Qian Robert J. Konrad 《Journal of lipid research》2022,63(5):100198
Triglycerides (TG) are required for fatty acid transport and storage and are essential for human health. Angiopoietin-like-protein 8 (ANGPTL8) has previously been shown to form a complex with ANGPTL3 that increases circulating TG by potently inhibiting LPL. We also recently showed that the TG-lowering apolipoprotein A5 (ApoA5) decreases TG levels by suppressing ANGPTL3/8-mediated LPL inhibition. To understand how LPL binds ANGPTL3/8 and ApoA5 blocks this interaction, we used hydrogen-deuterium exchange mass-spectrometry and molecular modeling to map binding sites of LPL and ApoA5 on ANGPTL3/8. Remarkably, we found that LPL and ApoA5 both bound a unique ANGPTL3/8 epitope consisting of N-terminal regions of ANGPTL3 and ANGPTL8 that are unmasked upon formation of the ANGPTL3/8 complex. We further used ANGPTL3/8 as an immunogen to develop an antibody targeting this same epitope. After refocusing on antibodies that bound ANGPTL3/8, as opposed to ANGPTL3 or ANGPTL8 alone, we utilized bio-layer interferometry to select an antibody exhibiting high-affinity binding to the desired epitope. We revealed an ANGPTL3/8 leucine zipper-like motif within the anti-ANGPTL3/8 epitope, the LPL-inhibitory region, and the ApoA5-interacting region, suggesting the mechanism by which ApoA5 lowers TG is via competition with LPL for the same ANGPTL3/8-binding site. Supporting this hypothesis, we demonstrate that the anti-ANGPTL3/8 antibody potently blocked ANGPTL3/8-mediated LPL inhibition in vitro and dramatically lowered TG levels in vivo. Together, these data show that an anti-ANGPTL3/8 antibody targeting the same leucine zipper-containing epitope recognized by LPL and ApoA5 markedly decreases TG by suppressing ANGPTL3/8-mediated LPL inhibition. 相似文献
538.
539.
Effect of protein calorie malnutrition and calcium deficiency on hepatic iso-metallothioneins in Cd-exposed monkeys 总被引:1,自引:0,他引:1
Oral administration of cadmium results in the induction of metallothionein in liver of rhesus monkeys subjected to protein calorie malnutrition and calcium deficiency. Metallothionein was resolved into three iso-proteins viz. MTa, MTb & MTc which varied in their quantities and metal composition in these nutritional stress conditions. 'MTc' was the major iso-protein in protein calorie malnourished monkeys, while 'MTb' predominated in the calcium deficient group. 相似文献
540.