全文获取类型
收费全文 | 2921篇 |
免费 | 248篇 |
专业分类
3169篇 |
出版年
2023年 | 9篇 |
2022年 | 33篇 |
2021年 | 44篇 |
2020年 | 31篇 |
2019年 | 45篇 |
2018年 | 52篇 |
2017年 | 34篇 |
2016年 | 68篇 |
2015年 | 137篇 |
2014年 | 169篇 |
2013年 | 168篇 |
2012年 | 241篇 |
2011年 | 227篇 |
2010年 | 117篇 |
2009年 | 119篇 |
2008年 | 179篇 |
2007年 | 182篇 |
2006年 | 160篇 |
2005年 | 159篇 |
2004年 | 172篇 |
2003年 | 157篇 |
2002年 | 146篇 |
2001年 | 41篇 |
2000年 | 24篇 |
1999年 | 37篇 |
1998年 | 44篇 |
1997年 | 39篇 |
1996年 | 24篇 |
1995年 | 27篇 |
1994年 | 21篇 |
1993年 | 28篇 |
1992年 | 23篇 |
1991年 | 17篇 |
1990年 | 21篇 |
1989年 | 16篇 |
1988年 | 15篇 |
1987年 | 15篇 |
1986年 | 13篇 |
1985年 | 15篇 |
1984年 | 9篇 |
1983年 | 13篇 |
1982年 | 12篇 |
1981年 | 6篇 |
1980年 | 12篇 |
1979年 | 5篇 |
1978年 | 7篇 |
1976年 | 6篇 |
1974年 | 5篇 |
1973年 | 5篇 |
1971年 | 5篇 |
排序方式: 共有3169条查询结果,搜索用时 15 毫秒
81.
Jan Plue Pieter De Frenne Kamal Acharya Jrg Brunet Olivier Chabrerie Guillaume Decocq Martin Diekmann Bente J. Graae Thilo Heinken Martin Hermy Annette Kolb Isgard Lemke Jaan Liira Tobias Naaf Anna Shevtsova Kris Verheyen Monika Wulf Sara A. O. Cousins 《Global Ecology and Biogeography》2013,22(10):1106-1117
82.
Juliane Dinter Jessica Mühlhaus Carolin Leonie Wienchol Chun-Xia Yi Daniela Nürnberg Silke Morin Annette Grüters Josef K?hrle Torsten Sch?neberg Matthias Tsch?p Heiko Krude Gunnar Kleinau Heike Biebermann 《PloS one》2015,10(2)
ObjectiveApplication of 3-iodothyronamine (3-T1AM) results in decreased body temperature and body weight in rodents. The trace amine-associated receptor (TAAR) 1, a family A G protein-coupled receptor, is a target of 3-T1AM. However, 3-T1AM effects still persist in mTaar1 knockout mice, which suggest so far unknown further receptor targets that are of physiological relevance. TAAR5 is a highly conserved TAAR subtype among mammals and we here tested TAAR5 as a potential 3-T1AM target. First, we investigated mouse Taar5 (mTaar5) expression in several brain regions of the mouse in comparison to mTaar1. Secondly, to unravel the full spectrum of signaling capacities, we examined the distinct Gs-, Gi/o-, G12/13-, Gq/11- and MAP kinase-mediated signaling pathways of mouse and human TAAR5 under ligand-independent conditions and after application of 3-T1AM. We found overlapping localization of mTaar1 and mTaar5 in the amygdala and ventromedial hypothalamus of the mouse brain. Second, the murine and human TAAR5 (hTAAR5) display significant basal activity in the Gq/11 pathway but show differences in the basal activity in Gs and MAP kinase signaling. In contrast to mTaar5, 3-T1AM application at hTAAR5 resulted in significant reduction in basal IP3 formation and MAP kinase signaling. In conclusion, our data suggest that the human TAAR5 is a target for 3-T1AM, exhibiting inhibitory effects on IP3 formation and MAP kinase signaling pathways, but does not mediate Gs signaling effects as observed for TAAR1. This study also indicates differences between TAAR5 orthologs with respect to their signaling profile. In consequence, 3-T1AM-mediated effects may differ between rodents and humans. 相似文献
83.
Chaoying Hu Debra Tompson Mindy Magee Qian Chen Yan Mei Liu Wenjing Zhu Hongxin Zhao Annette S. Gross Yun Liu 《PloS one》2015,10(10)
Background and Objectives
Darapladib is a lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitor. This study evaluated the pharmacokinetics, pharmacodynamics and safety of darapladib in healthy Chinese subjects.Methods
Twenty-four subjects received darapladib 160 mg orally, approximately 1 hour after a standard breakfast, as a single dose and once daily for 28 days. Non-compartmental methods were used to determine the single and multiple dose pharmacokinetics of darapladib and its metabolite SB-553253. Repeat dose Lp-PLA2 activity and safety were evaluated.Results
Systemic exposure (AUC(0-T), Cmax geometric mean (CVb%)) of darapladib was higher after multiple-dosing (519 ng.h/mL (33.3%), 34.4 ng/mL (49.9%)) compared to single-dose administration (153 ng.h/mL (69.0%), 17.9 ng/mL (55.2%). The steady-state accumulation ratio was less than unity (Rs = 0.80), indicating time-dependent pharmacokinetics of darapladib. Darapladib steady-state was reached by Day 14 of once daily dosing. Systemic exposure to SB-553253 was lower than darapladib with median (SB-553253: darapladib) ratios for AUC(0-τ) of 0.0786 for single dose and 0.0532 for multiple dose administration. On Day 28, pre-dose and maximum inhibition of Lp-PLA2 activity was approximately 70% and 75% relative to the baseline value, respectively and was dependent of darapladib concentration. The most common adverse events (≥ 21% subjects) were abnormal faeces, abnormal urine odour, diarrhoea and nasopharyngitis.Conclusion
Darapladib 160 mg single and repeat doses were profiled in healthy Chinese subjects. Single dose systemic exposure to darapladib in healthy Chinese subjects was consistent with that observed previously in Western subjects whereas steady-state systemic exposure was approximately 65% higher in Chinese than Western subjects. The Lp-PLA2 activity and adverse event profile were similar in healthy Chinese and previous reports in Western subjects. Ethnic-specific dose adjustment of darapladib is not considered necessary for the Chinese population.Trial Registration
ClinicalTrials.gov NCT02000804 相似文献84.
Braun D Wirth EK Wohlgemuth F Reix N Klein MO Grüters A Köhrle J Schweizer U 《The Biochemical journal》2011,439(2):249-255
LAT2 (system L amino acid transporter 2) is composed of the subunits Slc7a8/Lat2 and Slc3a2/4F2hc. This transporter is highly expressed along the basolateral membranes of absorptive epithelia in kidney and small intestine, but is also abundant in the brain. Lat2 is an energy-independent exchanger of neutral amino acids, and was shown to transport thyroid hormones. We report in the present paper that targeted inactivation of Slc7a8 leads to increased urinary loss of small neutral amino acids. Development and growth of Slc7a8(-/-) mice appears normal, suggesting functional compensation of neutral amino acid transport by alternative transporters in kidney, intestine and placenta. Movement co-ordination is slightly impaired in mutant mice, although cerebellar development and structure remained inconspicuous. Circulating thyroid hormones, thyrotropin and thyroid hormone-responsive genes remained unchanged in Slc7a8(-/-) mice, possibly because of functional compensation by the thyroid hormone transporter Mct8 (monocarboxylate transporter 8), which is co-expressed in many cell types. The reason for the mild neurological phenotype remains unresolved. 相似文献
85.
86.
Hall JV Schell M Dessus-Babus S Moore CG Whittimore JD Sal M Dill BD Wyrick PB 《Cellular microbiology》2011,13(8):1183-1199
The oestrogen receptor (ER) α-β+ HEC-1B and the ERα+β+ Ishikawa (IK) cell lines were investigated to dissect the effects of oestrogen exposure on several parameters of Chlamydia trachomatis infection. Antibody blockage of ERα or ERβ alone or simultaneously significantly decreased C. trachomatis infectivity (45-68%). Addition of the ERβ antagonist, tamoxifen, to IK or HEC-1B prior to or after chlamydial infection caused a 30-90% decrease in infectivity, the latter due to disrupted eukaryotic organelles. In vivo, endometrial glandular epithelial cells are stimulated by hormonally influenced stromal signals. Accordingly, chlamydial infectivity was significantly increased by 27% and 21% in IK and HEC-1B cells co-cultured with SHT-290 stromal cells exposed to oestrogen. Endometrial stromal cell/epithelial cell co-culture revealed indirect effects of oestrogen on phosphorylation of extracellular signal-regulated kinase and calcium-dependant phospholipase A2 and significantly increased production of interleukin (IL)-8 and IL-6 in both uninfected and chlamydiae-infected epithelial cells. These results indicate that oestrogen and its receptors play multiple roles in chlamydial infection: (i) membrane oestrogen receptors (mERs) aid in chlamydial entry into host cells, and (ii) mER signalling may contribute to inclusion development during infection. Additionally, enhancement of chlamydial infection is affected by hormonally influenced stromal signals in conjunction with direct oestrogen stimulation of the human epithelia. 相似文献
87.
Localized H3K36 methylation states define histone H4K16 acetylation during transcriptional elongation in Drosophila 总被引:1,自引:0,他引:1
88.
89.
In Lake Constance, after several decades of cutrophication, a decrease in phosphorus loading over the last decade has lead to a partial recovery from eutrophication. Here we analyse the shift in the taxonomic composition of phytoplankton during the first decade of oligotrophication in Lake Constance. During the 1980s, spring total P concentrations decreased from ca. 130 to less than 50 ·l–1. This decrease was reflected by an approximately proportional decrease in summer phytoplankton biomass while spring phytoplankton biomass seemed unresponsive. Major taxonomic changes occured during both growth seasons. In spring, the proportion of diatoms, green algae and Chrysophyta increased while the proportion of Cryptophyta decreased. The summer trend was very different: the relative importance of diatoms decreased and Cryptophyta and Chrysophyta increased, while Chlorophyta reached their peak around 1985. These trends are also analysed at the genus level. Comparison with taxonomic trends during the eutrophication period shows the expected reversals in most cases. Comparison with other lakes shows general similarities, with the notable exception that Planktothrix rubescens has never been important in Lake Constance. The increase of diatoms during spring is attributed to their improved competitive performance with increasing Si:P ratios. Their decrease during summer is explained by the increasing silicate removal from the epilimnion by increasing spring populations. 相似文献
90.
Pichert A Samsonov SA Theisgen S Thomas L Baumann L Schiller J Beck-Sickinger AG Huster D Pisabarro MT 《Glycobiology》2012,22(1):134-145
The interactions between glycosaminoglycans (GAGs), important components of the extracellular matrix, and proteins such as growth factors and chemokines play critical roles in cellular regulation processes. Therefore, the design of GAG derivatives for the development of innovative materials with bio-like properties in terms of their interaction with regulatory proteins is of great interest for tissue engineering and regenerative medicine. Previous work on the chemokine interleukin-8 (IL-8) has focused on its interaction with heparin and heparan sulfate, which regulate chemokine function. However, the extracellular matrix contains other GAGs, such as hyaluronic acid (HA), dermatan sulfate (DS) and chondroitin sulfate (CS), which have so far not been characterized in terms of their distinct molecular recognition properties towards IL-8 in relation to their length and sulfation patterns. NMR and molecular modeling have been in great part the methods of choice to study the structural and recognition properties of GAGs and their protein complexes. However, separately these methods have challenges to cope with the high degree of similarity and flexibility that GAGs exhibit. In this work, we combine fluorescence spectroscopy, NMR experiments, docking and molecular dynamics simulations to study the configurational and recognition properties of IL-8 towards a series of HA and CS derivatives and DS. We analyze the effects of GAG length and sulfation patterns in binding strength and specificity, and the influence of GAG binding on IL-8 dimer formation. Our results highlight the importance of combining experimental and theoretical approaches to obtain a better understanding of the molecular recognition properties of GAG-protein systems. 相似文献