全文获取类型
收费全文 | 1348篇 |
免费 | 31篇 |
国内免费 | 38篇 |
出版年
2023年 | 10篇 |
2022年 | 23篇 |
2021年 | 18篇 |
2020年 | 32篇 |
2019年 | 39篇 |
2018年 | 47篇 |
2017年 | 22篇 |
2016年 | 28篇 |
2015年 | 28篇 |
2014年 | 54篇 |
2013年 | 92篇 |
2012年 | 28篇 |
2011年 | 86篇 |
2010年 | 39篇 |
2009年 | 56篇 |
2008年 | 74篇 |
2007年 | 64篇 |
2006年 | 63篇 |
2005年 | 47篇 |
2004年 | 50篇 |
2003年 | 36篇 |
2002年 | 28篇 |
2001年 | 24篇 |
2000年 | 17篇 |
1999年 | 31篇 |
1998年 | 17篇 |
1997年 | 17篇 |
1996年 | 14篇 |
1995年 | 22篇 |
1994年 | 13篇 |
1993年 | 28篇 |
1992年 | 16篇 |
1991年 | 20篇 |
1990年 | 15篇 |
1989年 | 12篇 |
1988年 | 22篇 |
1987年 | 19篇 |
1986年 | 14篇 |
1985年 | 26篇 |
1984年 | 24篇 |
1983年 | 20篇 |
1982年 | 20篇 |
1981年 | 7篇 |
1980年 | 8篇 |
1979年 | 14篇 |
1978年 | 9篇 |
1977年 | 6篇 |
1976年 | 5篇 |
1973年 | 5篇 |
1971年 | 3篇 |
排序方式: 共有1417条查询结果,搜索用时 609 毫秒
111.
Konopska B Gburek J Gołab K Warwas M 《Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology》2007,146(4):482-488
Chicken cystatin, a homologue of human cystatin C, like other low-molecular-weight proteins is metabolized by renal proximal tubule cells. However, the precise mechanism(s) of this process has not been elucidated yet. To characterize chicken cystatin binding to renal brush-border membranes, the incubation of fluorescein labelled protein with rat cortical homogenate was performed. Saturation-dependent and reversible binding with low affinity (Kd = 3.67–4.07 μM) and high capacity (Bmax = 2.32–2.79 nmol/mg) was observed. Bovine albumin was the most potent competitor (Ki = 0.7 μM) among other megalin/cubilin ligands tested. The presence of Ca+ 2 ions was necessary to effective cystatin binding by brush-border membranes. Obtained data strongly support the hypothesis that chicken cystatin is a novel ligand for megalin/cubilin receptors tandem on proximal tubular cells. 相似文献
112.
Conditions were evaluated for optimum cryopreservation of primary chicken embryo kidney (CEK) cells. The recovery of viable
CEK cells was best (50.8% viability) when the concentration of dimethyl sulfoxide (DMSO) in the freezing medium was 20% (v/v).
The viability of primary CEK cells was not influenced by the concentration of calf serum in the freezing medium, the duration
of storage at −70°C before storage in liquid nitrogen, cell concentration, or the method of addition or dilution of DMSO.
Thawed cells recovered and grew in complete growth medium similarly to cells freshly isolated from kidney, and influenza viruses
produced plaques in the monolayer. The cryopreservation procedures described here may facilitate maintenance of a standard
stock of primary CEK cells for laboratories where preparation of primary CEK cells is not an option. 相似文献
113.
《European journal of cell biology》2022,101(4):151280
Early discover of risk progression of invisible carcinomas is important for a prerequisite successful treatment. Here, we investigated whether concentration of human thymidine kinase 1 (HTK1) discover invisible malignant human tumours. The HTK1 concentration of tumour cellular based on HTK1 IgY-polyclonal-antibody (HTK1-IgY-pAb) was determined by using a novel automatic chemiluminescence analyser with sandwich biotin-streptavidin (SBSA) platform. Minimum number of cells able to be detected by this technology used cells with low and high concentration of HTK1. The limit visibility by tumour imaging is approximately 1 mm in diameter, corresponding to approximately 109 cells with a cell diameter of 1 µm. Based on a HTK1 standard curve and a molecular weight of HTK1 of 96 kD, the HTK1protein (HTK1p) concentration per cell was calculated to be 0.021 pg. Assuming 200 pg in total protein/cell, approximately 50 × 106 growing malignant cells in the body were calculated to releases HTK1 into 5-liter blood. A HTK1 values of 3.914, 0.435 and 0.009 pmol/L corresponds to 10 × 105, 2 × 105 and 1 × 105 growing malignant cells, respectively. The lowest detectable sensitivity of HTK1 is 0.009 pmol/L in 1 × 105 growing malignant cells and 0.01 pmol/L in blood serum, detectable in health screening. Comparing the novel automatic chemiluminescence analyser with the original ECL dot-blot assay using serum HTK1p (health screening, n = 265) showed high correlation (r = 0.8743, P < .000). In conclusion, the novel automatic chemiluminescence analyser with SBSA platform is a reliable method with high accuracy to determine carcinoma invisible. 相似文献
114.
Lysosomal photosensitizers have been used in photodynamic therapy. The combination of such photosensitizers and light causes lysosomal photodamage, inducing cell death. Lysosomal disruption can lead to apoptosis but its signaling pathways remain to be elucidated. In this study, N-aspartyl chlorin e6 (NPe6), an effective photosensitizer that preferentially accumulates in lysosomes, was used to study the mechanism of apoptosis caused by lysosomal photodamage. Apoptosis in living human lung adenocarcinoma cells (ASTC-a-1) after NPe6-photodynamic treatment (NPe6-PDT) was studied using real-time single-cell analysis. Our results demonstrated that NPe6-PDT induced rapid generation of reactive oxygen species (ROS). The photodynamically produced ROS caused a rapid destruction of lysosomes, leading to release of cathepsins, and the ROS scavengers vitamin C and NAC prevent the effects. Then the following spatiotemporal sequence of cellular events was observed during cell apoptosis: Bcl-2-associated X protein (Bax) activation, cytochrome c release, and caspase-9/-3 activation. Importantly, the activation of Bax proved to be a crucial event in this apoptotic machinery, because suppressing the endogenous Bax using siRNA could significantly inhibit cytochrome c release and caspase-9/-3 activation and protect the cell from death. In conclusion, this study demonstrates that PDT with lysosomal photosensitizer induces Bax activation and subsequently initiates the mitochondrial apoptotic pathway. 相似文献
115.
Lebois EP Digby GJ Sheffler DJ Melancon BJ Tarr JC Cho HP Miller NR Morrison R Bridges TM Xiang Z Daniels JS Wood MR Conn PJ Lindsley CW 《Bioorganic & medicinal chemistry letters》2011,21(21):6451-6455
Herein we report the discovery and SAR of a novel series of M(1) agonists based on the MLPCN probe, ML071. From this, VU0364572 emerged as a potent, orally bioavailable and CNS penetrant M(1) agonist with high selectivity, clean ancillary pharmacology and enantiospecific activity. 相似文献
116.
Watson C Owen DR Harding D Kon-I K Lewis ML Mason HJ Matsumizu M Mukaiyama T Rodriguez-Lens M Shima A Takeuchi M Tran I Young T 《Bioorganic & medicinal chemistry letters》2011,21(14):4284-4287
A series of benzimidazole CB2 receptor agonists were prepared and their properties investigated. Optimisation of the three benzimidazole substituents led to the identification of compound 23, a potent CB2 full agonist (EC50 2.7 nM) with excellent selectivity over the CB1 receptor (>3000-fold). Compound 23 demonstrated good CNS penetration in rat. Further optimisation led to the identification of compound 34 with improved selectivity over hERG and excellent CNS penetration in rat. 相似文献
117.
Lim KS Kang DW Kim YS Kim MS Park SG Choi S Pearce LV Blumberg PM Lee J 《Bioorganic & medicinal chemistry letters》2011,21(1):299-302
A series of 5′-halogenated resiniferatoxin analogs have been investigated in order to examine the effect of halogenation in the A-region on their binding and the functional pattern of agonism/antagonism for rat TRPV1 heterologously expressed in Chinese hamster ovary cells. Halogenation at the 5-position in the A-region of RTX and of 4-amino RTX shifted the agonism of parent compounds toward antagonism. The extent of antagonism was greater as the size of the halogen increased (I > Br > Cl > F) while the binding affinities were similar, as previously observed for our potent agonists. In this series, 5-bromo-4-amino RTX (39) showed very potent antagonism with Ki (ant) = 2.81 nM, which was thus 4.5-fold more potent than 5′-iodo RTX, previously reported as a potent TRPV1 antagonist. Molecular modeling analyses with selected agonists and the corresponding halogenated antagonists revealed a striking conformational difference. The 3-methoxy of the A-region in the agonists remained free to interact with the receptor whereas in the case of the antagonists, the compounds assumed a bent conformation, permitting the 3-methoxy to instead form an internal hydrogen bond with the C4-hydroxyl of the diterpene. 相似文献
118.
Packiarajan M Marzabadi MR Desai M Lu Y Noble SA Wong WC Jubian V Chandrasena G Wolinsky TD Zhong H Walker MW Wiborg O Andersen K 《Bioorganic & medicinal chemistry letters》2011,21(18):5436-5441
The structure-activity relationship of a series of tricyclic-sulfonamide compounds 11-32 culminating in the discovery of N-[trans-4-(4,5-dihydro-3,6-dithia-1-aza-benzo[e]azulen-2-ylamino)-cyclohexylmethyl]-methanesulfonamide (15, Lu AA33810) is reported. Compound 15 was identified as a selective and high affinity NPY5 antagonist with good oral bioavailability in mice (42%) and rats (92%). Dose dependent inhibition of feeding was observed after i.c.v. injection of the selective NPY5 agonist ([cPP(1-7),NPY(19-23),Ala(31),Aib(32),Gln(34)]-hPP). In addition, ip administration of Lu AA33810 (10 mg/kg) produced antidepressant-like effects in a rat model of chronic mild stress. 相似文献
119.
Ratcliffe P Adam JM Baker J Bursi R Campbell R Clark JK Cottney JE Deehan M Easson AM Ecker D Edwards D Epemolu O Evans L Fields R Francis S Harradine P Jeremiah F Kiyoi T McArthur D Morrison A Passier P Pick J Schnabel PG Schulz J Steinbrede H Walker G Westwood P Wishart G de Haes JU 《Bioorganic & medicinal chemistry letters》2011,21(8):2541-2546
We report an expansion of the structure-activity relationship (SAR) of a novel series of indole-3-heterocyclic CB1 receptor agonists. Starting from the potent but poorly soluble lead, 1, a rational approach was taken in order to balance solubility, hERG activity and potency while retaining the desired long duration of action within the mouse tail flick test. This led to the discovery of compound 38 which successfully progressed into clinical development. 相似文献
120.
Tran TD Pryde DC Jones P Adam FM Benson N Bish G Calo F Ciaramella G Dixon R Duckworth J Fox DN Hay DA Hitchin J Horscroft N Howard M Gardner I Jones HM Laxton C Parkinson T Parsons G Proctor K Smith MC Smith N Thomas A 《Bioorganic & medicinal chemistry letters》2011,21(8):2389-2393
The synthesis and structure-activity relationships of a series of novel interferon inducers are described. Pharmacokinetic studies and efficacy assessment of a series of 8-oxo-3-deazapurine analogues led to the identification of compound 33, a potent and selective agonist of the TLR7 receptor with an excellent in vivo efficacy profile in a mouse model. 相似文献