全文获取类型
收费全文 | 2895篇 |
免费 | 86篇 |
国内免费 | 42篇 |
学科分类
生物科学 | 3023篇 |
出版年
2023年 | 15篇 |
2022年 | 10篇 |
2021年 | 21篇 |
2020年 | 29篇 |
2019年 | 54篇 |
2018年 | 80篇 |
2017年 | 45篇 |
2016年 | 24篇 |
2015年 | 31篇 |
2014年 | 107篇 |
2013年 | 217篇 |
2012年 | 78篇 |
2011年 | 146篇 |
2010年 | 102篇 |
2009年 | 131篇 |
2008年 | 132篇 |
2007年 | 137篇 |
2006年 | 132篇 |
2005年 | 103篇 |
2004年 | 82篇 |
2003年 | 58篇 |
2002年 | 69篇 |
2001年 | 42篇 |
2000年 | 45篇 |
1999年 | 47篇 |
1998年 | 49篇 |
1997年 | 48篇 |
1996年 | 44篇 |
1995年 | 35篇 |
1994年 | 49篇 |
1993年 | 41篇 |
1992年 | 56篇 |
1991年 | 47篇 |
1990年 | 47篇 |
1989年 | 50篇 |
1988年 | 40篇 |
1987年 | 60篇 |
1986年 | 39篇 |
1985年 | 69篇 |
1984年 | 81篇 |
1983年 | 61篇 |
1982年 | 68篇 |
1981年 | 38篇 |
1980年 | 44篇 |
1979年 | 21篇 |
1978年 | 17篇 |
1977年 | 26篇 |
1975年 | 11篇 |
1974年 | 18篇 |
1973年 | 13篇 |
排序方式: 共有3023条查询结果,搜索用时 125 毫秒
1.
《Bioorganic & medicinal chemistry letters》2020,30(16):127289
The present research project details synthesis of new hybrid methanofullerenes based on acetylene and triazole esters of malonic acid containing 5Z,9Z-dienoic acids and fullerene C60 under Bingel-Hirsch conditions, including study of the cytotoxic activity with respect to Jurkat, K562, U937 and HL60 tumor cell lines. Hybrid methanofullerenes containing acetylenic fragments, unlike triazole substituents, were found to exhibit higher cytotoxicity, but are characterized by lower selectivity of action in relation to healthy cells. 相似文献
2.
Abstract: In membranes of rat olfactory bulb, a brain region in which muscarinic agonists increase cyclic AMP formation, the muscarinic stimulation of guanosine 5'- O -(3-[35 S]thiotriphosphate) ([35 S]GTPγS) binding was used as a tool to investigate the receptor interaction with the guanine nucleotide-binding regulatory proteins (G proteins). The stimulation of the radioligand binding by carbachol (CCh) was optimal (threefold increase) in the presence of micromolar concentrations of GDP and 100 m M NaCl. Exposure to N -ethylmaleimide and pertussis toxin markedly inhibited the CCh effect, whereas it increased the relative stimulation of [35 S]GTPγS binding elicited by pituitary adenylate cyclase-activating polypeptide (PACAP). On the other hand, membrane treatment with cholera toxin curtailed the PACAP stimulation of [35 S]GTPγS binding but did not affect the response to CCh. Like CCh, a number of cholinergic agonists stimulated [35 S]GTPγS binding in a concentration-dependent and saturable manner. The antagonist profile of the muscarinic stimulation of [35 S]GTPγS binding was highly correlated with that displayed by the muscarinic stimulation of adenylyl cyclase. These data indicate that the olfactory bulb muscarinic receptors couple to Gi /Go , but not to Gs , and support the possibility that activation of Gi /Go mediates the stimulatory effect on adenylyl cyclase activity. 相似文献
3.
《Bioorganic & medicinal chemistry》2020,28(24):115819
The exploitation of GLU988 and LYS903 residues in PARP1 as targets to design isoquinolinone (I & II) and naphthyridinone (III) analogues is described. Compounds of structure I have good biochemical and cellular potency but suffered from inferior PK. Constraining the linear propylene linker of structure I into a cyclopentene ring (II) offered improved PK parameters, while maintaining potency for PARP1. Finally, to avoid potential issues that may arise from the presence of an anilinic moiety, the nitrogen substituent on the isoquinolinone ring was incorporated as part of the bicyclic ring. This afforded a naphthyridinone scaffold, as shown in structure III. Further optimization of naphthyridinone series led to identification of a novel and highly potent PARP1 inhibitor 34, which was further characterized as preclinical candidate molecule. Compound 34 is orally bioavailable and displayed favorable pharmacokinetic (PK) properties. Compound 34 demonstrated remarkable antitumor efficacy both as a single-agent as well as in combination with chemotherapeutic agents in the BRCA1 mutant MDA-MB-436 breast cancer xenograft model. Additionally, compound 34 also potentiated the effect of agents such as temozolomide in breast cancer, pancreatic cancer and Ewing’s sarcoma models. 相似文献
4.
Liver plasma membranes prepared from genetically diabetic (db/db) mice expressed levels of Gi α-2, Gi α-3 and G-protein β-subunits that were reduced by some 75, 63 and 73% compared with levels seen in membranes from lean animals. In contrast, there were no significant differences in the expression of the 42 and 45 kDa forms of Gs α-subunits. Pertussis toxin-catalysed ADP-ribosylation of membranes from lean animals identified a single 41 kDa band whose labelling was reduced by some 86% in membranes from diabetic animals. Cholera toxin-catalysed ADP-ribosylation identified two forms of Gs α-subunits whose labelling was about 4-fold greater in membranes from diabetic animals compared with those from lean animals. Maximal stimulations of adenylyl cyclase activity by forskolin (100 μM), GTP (100 μM), p[NH]ppG (100 μM), NaF (10 mM) and glucagon (10 μM) were similar in membranes from lean and diabetic animals, whereas stimulation by isoprenaline (100 μM) was lower by about 22%. Lower concentrations (EC50-60 nM) of p[NH]ppG were needed to activate adenylyl cyclase in membranes from diabetic animals compared to those from lean animals (EC50-158 nM). As well as causing activation, p[NH]ppG was capable of eliciting a pertussis toxin-sensitive inhibitory effect upon forskolin-stimulated adenylyl cyclase activity in membranes from both lean and diabetic animals. However, maximal inhibition of adenylyl cyclase activity in membranes from diabetic animals was reduced to around 60% of that found using membranes from lean animals. Pertussis toxin-treatment in vivo enhanced maximal stimulation of adenylyl cyclase by glucagon, isoprenaline and p[NH]ppG through a process suggested to be mediated by the abolition of functional Gi activity. The lower levels of expression of G-protein β-subunits, in membranes from diabetic compared with lean animals, is suggested to perturb the equilibria between holomeric and dissociated G-protein subunits. We suggest that this may explain both the enhanced sensitivity of adenylyl cyclase to stimulation by p[NH]ppG in membranes from diabetic animals and the altered ability of pertussis and cholera toxins to catalyse the ADP-ribosylation of G-proteins in membranes from these two animals. 相似文献
5.
Macarena Sahores Alessandro Prinetti Francesco Blasi Sandro Sonnino 《生物化学与生物物理学报:生物膜》2008,1778(1):250-259
UPAR is a GPI anchored protein, which is found in both lipid rafts and in more fluid regions of the plasma membrane. We have studied the role of the ligand uPA on uPAR localization and on the composition of the lipid membrane microdomains. We have analyzed the glycosphingolipid environment of uPAR in detergent resistant membrane (DRM) fractions prepared by cell lysis with 1% Triton X-100 and fractionated by sucrose gradient centrifugation obtained from HEK293-uPAR cells. The uPAR specific lipid membrane microdomain has been separated from the total DRM fraction by immunoprecipitation with an anti-uPAR specific antibody under conditions that preserve membrane integrity. We have also tested uPA-induced ERK phosphorylation in the presence of methyl-β-cyclodextrin, which is known to disrupt lipid rafts by sequestering cholesterol from such domains. Our results show that uPAR is partially associated with DRM and this association is increased by ligands, is independent of the catalytic activity of uPA, and is required for intracellular signalling. In the absence of ligands, uPAR experiences a lipid environment very similar to that of total DRM, enriched in sphingomyelin and glycosphingolipids. However, after treatment of cells with uPA or ATF the lipid environment is strongly impoverished of neutral glycosphingolipids. 相似文献
6.
Lan-Ying Qin Zheming Ruan Robert J. Cherney T.G. Murali Dhar James Neels Carolyn A. Weigelt John S. Sack Anurag S. Srivastava Lyndon A.M. Cornelius Joseph A. Tino Kevin Stefanski Xiaomei Gu Jenny Xie Vojkan Susulic Xiaoxia Yang Melissa Yarde-Chinn Stacey Skala Ruth Bosnius Michael A. Poss 《Bioorganic & medicinal chemistry letters》2017,27(4):855-861
As demonstrated in preclinical animal models, the disruption of PI3Kδ expression or its activity leads to a decrease in inflammatory and immune responses. Therefore, inhibition of PI3Kδ may provide an alternative treatment for autoimmune diseases, such as RA, SLE, and respiratory ailments. Herein, we disclose the identification of 7-(3-(piperazin-1-yl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine derivatives as highly potent, selective and orally bioavailable PI3Kδ inhibitors. The lead compound demonstrated efficacy in an in vivo mouse KLH model. 相似文献
7.
Identification of sodC encoding periplasmic [Cu,Zn]-superoxide dismutase in Salmonella 总被引:3,自引:0,他引:3
James Canvin Paul R. Langford Kathryn E. Wilks J. Simon Kroll 《FEMS microbiology letters》1996,136(2):215-220
Abstract sodC , encoding [Cu,Zn]-cofactored Superoxide dismutase, once thought to be virtually confined to eukaryotes, has now been described in many Gram-negative pathogens that have their primary niche of colonization in the upper respiratory tract. Their role in host-parasite interactive biology is unknown. We here show that members of the major human and animal enteric pathogenic species Salmonella harbour a version of sodC most closely resembling that found in Brucella abortus . The enzyme it encodes is a novel candidate determinant of virulence in Salmonella , an intracellular pathogen potentially exposed to toxic oxygen free radicals within its intracellular niche. 相似文献
8.
9.
《Bioorganic & medicinal chemistry letters》2020,30(9):127067
Adenosine pathway, including its generating enzyme (CD73) and its receptors represents a key target for cancer immunotherapy. Here we aimed to search for novel compounds able to co-target the CD73 and the A2A adenosine receptor (A2A AR) as dual-blockers of adenosine generation and activity. The design project was to combine in the same molecule the thiazolo[5,4-d]pyrimidine core, an essential pharmacophoric feature to block the A2A AR, with a benzenesulfonamide group which is a characteristic group of CD73 inhibitors. Most of the reported compounds resulted in inverse agonists of the human (h) A2A AR endowed with high affinity, selectivity and potency. However they were weak inhibitors of CD73 enzyme. Nevertheless, this study can be considered as a starting point to develop more active compounds. 相似文献
10.
The impact of elevated CO2 and global
climate change on arbuscular mycorrhizas: a mycocentric approach 总被引:2,自引:2,他引:0
Arbuscular mycorrhizal (AM) symbioses are a potentially important link in the chain of response of ecosystems to elevated atmospheric [CO2 ]. By promoting plant phosphorus uptake and acting as a sink for plant carbon, they can alleviate photosynthetic down-regulation. Because hyphal turnover is likely to be fast, especially in warmer soils, they can also act as a rapid pathway for the return of carbon to the atmosphere. However, most experiments on AM responses to [CO2 ] have failed to take into account the difference in growth of mycorrhizal and non- mycorrhizal plants; those that have done so suggest that AM colonization of roots is little altered by [CO2 ], although this issue remains to be resolved. Very little is known about the effects of other factors of global environmental change on mycorrhizas. These issues need urgent attention. It is also necessary to understand the potential for the various AM fungal taxa to respond differentially to environmental changes, including carbon supply and soil temperature and moisture, especially because of the differential abilities of plant and fungal species to migrate in response to changing environments. Indeed, there is a need for a new approach to the study of mycorrhizal associations, which has been too plant-centred. It is essential to regard the fungus as an organism itself, and to understand its biology both as an entity and as part of a symbiosis. 相似文献