全文获取类型
收费全文 | 1651篇 |
免费 | 125篇 |
出版年
2023年 | 4篇 |
2022年 | 17篇 |
2021年 | 24篇 |
2020年 | 31篇 |
2019年 | 22篇 |
2018年 | 28篇 |
2017年 | 28篇 |
2016年 | 51篇 |
2015年 | 48篇 |
2014年 | 62篇 |
2013年 | 80篇 |
2012年 | 143篇 |
2011年 | 127篇 |
2010年 | 70篇 |
2009年 | 96篇 |
2008年 | 87篇 |
2007年 | 116篇 |
2006年 | 105篇 |
2005年 | 109篇 |
2004年 | 88篇 |
2003年 | 86篇 |
2002年 | 68篇 |
2001年 | 26篇 |
2000年 | 9篇 |
1999年 | 18篇 |
1998年 | 23篇 |
1997年 | 20篇 |
1996年 | 11篇 |
1995年 | 23篇 |
1994年 | 17篇 |
1993年 | 14篇 |
1992年 | 8篇 |
1991年 | 5篇 |
1990年 | 9篇 |
1989年 | 7篇 |
1988年 | 5篇 |
1987年 | 4篇 |
1986年 | 4篇 |
1985年 | 9篇 |
1984年 | 8篇 |
1983年 | 6篇 |
1982年 | 4篇 |
1981年 | 3篇 |
1979年 | 4篇 |
1977年 | 11篇 |
1976年 | 7篇 |
1975年 | 5篇 |
1973年 | 4篇 |
1972年 | 4篇 |
1968年 | 3篇 |
排序方式: 共有1776条查询结果,搜索用时 46 毫秒
41.
Rainer Gewald Christian Grunwald Ute Egerland 《Bioorganic & medicinal chemistry letters》2013,23(15):4308-4314
Expanding on HTS hit 4 afforded a series of [1,3,5]triazine derivatives as novel PDE4 inhibitors. The SAR development and optimization process with the emphasis on ligand efficiency and physicochemical properties led to the discovery of compound 44 as a potent, selective and orally active PDE4 inhibitor. 相似文献
42.
David Fowler Mhairi Coyle Ute Skiba Mark A. Sutton J. Neil Cape Stefan Reis Lucy J. Sheppard Alan Jenkins Bruna Grizzetti James N. Galloway Peter Vitousek Allison Leach Alexander F. Bouwman Klaus Butterbach-Bahl Frank Dentener David Stevenson Marcus Amann Maren Voss 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2013,368(1621)
Global nitrogen fixation contributes 413 Tg of reactive nitrogen (Nr) to terrestrial and marine ecosystems annually of which anthropogenic activities are responsible for half, 210 Tg N. The majority of the transformations of anthropogenic Nr are on land (240 Tg N yr−1) within soils and vegetation where reduced Nr contributes most of the input through the use of fertilizer nitrogen in agriculture. Leakages from the use of fertilizer Nr contribute to nitrate (NO3−) in drainage waters from agricultural land and emissions of trace Nr compounds to the atmosphere. Emissions, mainly of ammonia (NH3) from land together with combustion related emissions of nitrogen oxides (NOx), contribute 100 Tg N yr−1 to the atmosphere, which are transported between countries and processed within the atmosphere, generating secondary pollutants, including ozone and other photochemical oxidants and aerosols, especially ammonium nitrate (NH4NO3) and ammonium sulfate (NH4)2SO4. Leaching and riverine transport of NO3 contribute 40–70 Tg N yr−1 to coastal waters and the open ocean, which together with the 30 Tg input to oceans from atmospheric deposition combine with marine biological nitrogen fixation (140 Tg N yr−1) to double the ocean processing of Nr. Some of the marine Nr is buried in sediments, the remainder being denitrified back to the atmosphere as N2 or N2O. The marine processing is of a similar magnitude to that in terrestrial soils and vegetation, but has a larger fraction of natural origin. The lifetime of Nr in the atmosphere, with the exception of N2O, is only a few weeks, while in terrestrial ecosystems, with the exception of peatlands (where it can be 102–103 years), the lifetime is a few decades. In the ocean, the lifetime of Nr is less well known but seems to be longer than in terrestrial ecosystems and may represent an important long-term source of N2O that will respond very slowly to control measures on the sources of Nr from which it is produced. 相似文献
43.
U Hofmann S Michaelis T Winckler J Wegener KH Feller 《Biosensors & bioelectronics》2013,39(1):156-162
This study presents the time-resolved detection of chemically induced stress upon intracellular signaling cascades by using genetically modified sensor cells based on the human keratinocyte cell line HaCaT. The cells were stably transfected with a HSP72-GFP reporter gene construct to create an optical sensor cell line expressing a stress-inducible reporter protein. The time- and dose-dependent performance of the sensor cells is demonstrated and discussed in comparison to a label-free impedimetric monitoring approach (electric cell-substrate impedance sensing, ECIS). Moreover, a microfluidic platform was established based on μSlidesI(0,4)Luer to allow for a convenient, sterile and incubator-independent time-lapse microscopic observation of the sensor cells. Cell growth was successfully achieved in this microfluidic setup and the cellular response to a cytotoxic substance could be followed in real-time and in a non-invasive, sensitive manner. This study paves the way for the development of micro-total analysis systems that combine optical and impedimetric readouts to enable an overall quantitative characterization of changes in cell metabolism and morphology as a response to toxin exposure. By recording multiple parameters, a detailed discrimination between competing stress- or growth-related mechanisms is possible, thereby presenting an entirely new in vitro alternative to skin irritation tests. 相似文献
44.
Seied Mojtaba Valiahdi Alexander E. Egger Walter Miklos Ute Jungwirth Kristof Meelich Petra Nock Walter Berger Christian G. Hartinger Markus Galanski Michael A. Jakupec Bernhard K. Keppler 《Journal of biological inorganic chemistry》2013,18(2):249-260
Extracellular acidity is a frequent pathophysiological condition of solid tumors offering possibilities for improving the tumor selectivity of molecular therapy. This might be accomplished by prodrugs with low systemic toxicity, attaining their full antitumor potency only under acidic conditions, such as bis(2-aminoalcoholato-κ²N,O)platinum(II) complexes that are activated by protonation of alcoholato oxygen, resulting in cleavage of platinum–oxygen bonds. In this work, we examined whether the pH dependency of such compounds is reflected in differential biological activity in vitro. In particular, the pH dependence of cytotoxicity, cellular accumulation, DNA platination, GMP binding, effects on DNA secondary structure, cell cycle alterations, and induction of apoptosis was investigated. Enhanced cytotoxicity of five of these complexes in non-small-cell lung cancer (A549) and colon carcinoma (HT-29) cells at pH 6.0 in comparison with pH 7.4 was confirmed: 50 % growth inhibition concentrations ranged from 42 to 214 μM in A549 cells and from 35 to 87 μM in HT-29 cells at pH 7.4 and decreased at pH 6.0 to 11–50 and 7.3–25 μM, respectively. The effects induced by all five pH-sensitive compounds involve increased 5′-GMP binding, cellular accumulation, and DNA platination as well as stronger effects on DNA secondary structure at pH 6.0 than at pH 7.4. As exemplified by treatment of A549 cells with a 2-amino-4-methyl-1-pentanolato complex, induction of apoptosis is enhanced at pH 6.5. These results confirm the increased reactivity and in vitro activity of these compounds under slightly acidic conditions, encouraging further evaluation of ring-closed aminoalcoholatoplatinum(II) derivatives in solid tumors in vivo. 相似文献
45.
Erawan Borkham-Kamphorst Eddy van de Leur Henning W. Zimmermann Karlin Raja Karlmark Lidia Tihaa Ute Haas Frank Tacke Thorsten Berger Tak W. Mak Ralf Weiskirchen 《生物化学与生物物理学报:疾病的分子基础》2013,1832(5):660-673
Lipocalin-2 is expressed under pernicious conditions such as intoxication, infection, inflammation and other forms of cellular stress. Experimental liver injury induces rapid and sustained LCN2 production by injured hepatocytes. However, the precise biological function of LCN2 in liver is still unknown. In this study, LCN2?/? mice were exposed to short term application of CCl4, lipopolysaccharide and Concanavalin A, or subjected to bile duct ligation. Subsequent injuries were assessed by liver function analysis, qRT-PCR for chemokine and cytokine expression, liver tissue Western blot, histology and TUNEL assay. Serum LCN2 levels from patients suffering from liver disease were assessed and evaluated. Acute CCl4 intoxication showed increased liver damage in LCN2?/? mice indicated by higher levels of aminotransferases, and increased expression of inflammatory cytokines and chemokines such as IL-1β, IL-6, TNF-α and MCP-1/CCL2, resulting in sustained activation of STAT1, STAT3 and JNK pathways. Hepatocytes of LCN2?/? mice showed lipid droplet accumulation and increased apoptosis. Hepatocyte apoptosis was confirmed in the Concanavalin A and lipopolysaccharide models. In chronic models (4 weeks bile duct ligation or 8 weeks CCl4 application), LCN2?/? mice showed slightly increased fibrosis compared to controls. Interestingly, serum LCN2 levels in diseased human livers were significantly higher compared to controls, but no differences were observed between cirrhotic and non-cirrhotic patients. Upregulation of LCN2 is a reliable indicator of liver damage and has significant hepato-protective effect in acute liver injury. LCN2 levels provide no correlation to the degree of liver fibrosis but show significant positive correlation to inflammation instead. 相似文献
46.
Lutz?HamannEmail author Alexander?Koch Saubashya?Sur Nadja?Hoefer Christiane?Glaeser Susanne?Schulz Michael?Gross Andre?Franke Ute?N?thlings Kai?Zacharowski Ralf?R?Schumann 《Immunity & ageing : I & A》2013,10(1):43
Background
The pro-inflammatory status of the elderly triggers most of the age-related diseases such as cancer and atherosclerosis. Atherosclerosis, the leading cause world wide of morbidity and death, is an inflammatory disease influenced by life-style and genetic host factors. Stimuli such as oxLDL or microbial ligands have been proposed to trigger inflammation leading to atherosclerosis. It has recently been shown that oxLDL activates immune cells via the Toll-like receptor (TLR) 4/6 complex. Several common single nucleotide polymorphisms (SNPs) of the TLR system have been associated with atherosclerosis. To investigate the role of TLR-6 we analyzed the association of the TLR-6 SNP Pro249Ser with atherogenesis.Results
Genotyping of two independent groups with CAD, as well as of healthy controls revealed a significant association of the homozygous genotype with a reduced risk for atherosclerosis (odds ratio: 0.69, 95% CI 0.51-0.95, P?=?0.02). In addition, we found a trend towards an association with the risk of restenosis after transluminal coronary angioplasty (odds ratio: 0.53, 95% CI 0.24-1.16, P?=?0.12). In addition, first evidence is presented that the frequency of this protective genotype increases in a healthy population with age. Taken together, our results define a role for TLR-6 and its genetic variations in modulating the inflammatory response leading to atherosclerosis.Conclusions
These results may lead to a better risk stratification, and potentially to an improved prophylactic treatment of high-risk populations. Furthermore, the protective effect of this polymorphism may lead to an increase of this genotype in the healthy elderly and may therefore be a novel genetic marker for the well-being during aging.47.
An infrared sensor analysing label‐free the secondary structure of the Abeta peptide in presence of complex fluids 下载免费PDF全文
Andreas Nabers Julian Ollesch Jonas Schartner Carsten Kötting Just Genius Ute Haußmann Hans Klafki Jens Wiltfang Klaus Gerwert 《Journal of biophotonics》2016,9(3):224-234
The secondary structure change of the Abeta peptide to beta‐sheet was proposed as an early event in Alzheimer's disease. The transition may be used for diagnostics of this disease in an early state. We present an Attenuated Total Reflection (ATR) sensor modified with a specific antibody to extract minute amounts of Abeta peptide out of a complex fluid. Thereby, the Abeta peptide secondary structure was determined in its physiological aqueous environment by FTIR‐difference‐spectroscopy. The presented results open the door for label‐free Alzheimer diagnostics in cerebrospinal fluid or blood. It can be extended to further neurodegenerative diseases.
48.
Yeshambel T. Nigatu Sijmen A. Reijneveld Peter de Jonge Elisabeth van Rossum Ute Bültmann 《PloS one》2016,11(2)
Background
Obesity and major depressive disorder (MDD)/anxiety disorders often co-occur and aggravate each other resulting in adverse health-related outcomes. As little is known about the potential effects of interaction between obesity and MDD and/or anxiety disorders on health-related quality of life (HR-QoL), this study was aimed at examining these combined effects.Methods
We collected data among N = 89,332 participants from the LifeLines cohort study. We categorized body weight using body mass index (kg/m2) as normal weight (18.5–24.99), overweight (25–29.9), mild obesity (30–34.9) and moderate/severe obesity (≥ 35); we measured abdominal obesity using a waist circumference of ≥102 and ≥ 88 cm for males and females, respectively. MDD and anxiety disorders were diagnosed with the Mini-International Neuropsychiatric Interview. HR-QoL was assessed using the RAND-36 questionnaire to compute physical and mental quality of life scores. We used binary logistic and linear regression analyses.Results
The combined effect of obesity and MDD and/or anxiety disorders on physical QoL was larger than the sum of their separate effects; regression coefficients, B (95%-confidence interval, 95%-CI) were: - 1.32 (-1.75; -0.90). However, the combined effect of obesity and major depression alone on mental QoL was less than the additive effect. With increasing body weight participants report poorer physical QoL; when they also have MDD and/or anxiety disorders participants report even poorer physical QoL. In persons without MDD and/or anxiety disorders, obesity was associated with a better mental QoL.Conclusions
Obesity and MDD and/or anxiety disorders act synergistically on physical and mental QoL. The management of MDD and/or anxiety disorders and weight loss may be important routes to improve HR-QoL. 相似文献49.
Socioeconomic status and anthropometric changes—A meta‐analytic approach from seven German cohorts 下载免费PDF全文
Johannes Haerting Saskia Hartwig Daniel Tiller Daniel Medenwald Susanne Vogt Barbara Thorand Rolf Holle Ursula Bachlechner Heiner Boeing Benedikt Merz Ute Nöthlings Sabrina Schlesinger Sabine Schipf Till Ittermann Nicole Aumann Anja Schienkiewitz Marjolein Haftenberger Karin H. Greiser Jasmine Neamat‐Allah Verena Katzke Alexander Kluttig 《Obesity (Silver Spring, Md.)》2016,24(3):710-718
50.
Ute Seeland Ahmad T. Nauman Alissa Cornelis Sabine Ludwig Mathias Dunkel Georgios Kararigas Vera Regitz-Zagrosek 《Biology of sex differences》2016,7(1):39