全文获取类型
收费全文 | 1537篇 |
免费 | 106篇 |
国内免费 | 1篇 |
出版年
2023年 | 9篇 |
2022年 | 23篇 |
2021年 | 45篇 |
2020年 | 28篇 |
2019年 | 40篇 |
2018年 | 39篇 |
2017年 | 32篇 |
2016年 | 53篇 |
2015年 | 79篇 |
2014年 | 89篇 |
2013年 | 118篇 |
2012年 | 122篇 |
2011年 | 139篇 |
2010年 | 67篇 |
2009年 | 78篇 |
2008年 | 86篇 |
2007年 | 82篇 |
2006年 | 64篇 |
2005年 | 78篇 |
2004年 | 56篇 |
2003年 | 59篇 |
2002年 | 42篇 |
2001年 | 25篇 |
2000年 | 13篇 |
1999年 | 17篇 |
1998年 | 14篇 |
1997年 | 12篇 |
1996年 | 8篇 |
1995年 | 12篇 |
1994年 | 11篇 |
1993年 | 9篇 |
1992年 | 9篇 |
1991年 | 7篇 |
1990年 | 9篇 |
1989年 | 10篇 |
1988年 | 6篇 |
1987年 | 4篇 |
1986年 | 6篇 |
1985年 | 6篇 |
1984年 | 8篇 |
1983年 | 4篇 |
1981年 | 3篇 |
1980年 | 4篇 |
1979年 | 3篇 |
1978年 | 2篇 |
1977年 | 2篇 |
1974年 | 3篇 |
1973年 | 2篇 |
1961年 | 1篇 |
1936年 | 1篇 |
排序方式: 共有1644条查询结果,搜索用时 15 毫秒
871.
Oliveira C Lopez-Olmeda JF Delgado MJ Alonso-Gómez AL Sánchez-Vázquez FJ 《Chronobiology international》2008,25(4):645-652
We localized melatonin binding sites in different brain regions (optic tectum, telencephalon, cerebellum, hypothalamus, olfactory bulbs, and medulla oblongata) of Senegal sole, a species of aquaculture interest, and checked day/night changes in density (B(max)) at mid-light (ZT06) and mid-dark (ZT18). Plasma melatonin was measured using a radioimmunoassay, while binding assays were performed using 2-[(125)I]iodomelatonin as a radioligand. Plasma melatonin concentrations were significantly lower at mid-light (189.5+/-46 pg/ml) than mid-dark (455.5+/-163 pg/ml). Values of B(max) were statistically significantly higher in the optic tectum (5.6+/-0.6 and 12.3+/-1 fmol/mg prot, at mid-light and mid-dark, respectively) and in the cerebellum (7.7+/-1.1 and 10.6+/-1.3 fmol/mg prot, at mid-light and mid-dark, respectively). Significant day/night differences were only observed in these two tissues. These results show for the first time the distribution of melatonin binding sites within the brain of a flatfish species and their lack of down-regulation. 相似文献
872.
Tzeng HP Fan J Vallejo JG Dong JW Chen X Houser SR Mann DL 《American journal of physiology. Heart and circulatory physiology》2008,294(3):H1490-H1496
High-mobility group box 1 (HMGB1) released from necrotic cells or macrophages functions as a late inflammatory mediator and has been shown to induce cardiovascular collapse during sepsis. Thus far, however, the effect(s) of HMGB1 in the heart are not known. We determined the effects of HMGB1 on isolated feline cardiac myocytes by measuring sarcomere shortening in contracting cardiac myocytes, intracellular Ca2+ transients by using fluo-3, and L-type calcium currents by using whole cell perforate configuration of the patch-clamp technique. Treatment of isolated myocytes with HMGB1 (100 ng/ml) resulted in a 70% decrease in sarcomere shortening and a 50% decrease in the height of the peak Ca2+ transient within 5 min (P < 0.01). The immediate negative inotropic effects of HMGB1 on cell contractility and calcium homeostasis were partially reversible upon washout of HMGB1. A significant inhibition of the inward l-type calcium currents was also documented by the patch-clamp technique. HMGB1 induced the PKC-epsilon translocation, and a PKC inhibitor significantly attenuated the negative inotropic effects of HMGB1. These studies show for the first time that HMGB1 impairs sarcomere shortening by decreasing calcium availability in cardiac myocytes through modulating membrane calcium influx and suggest that HMGB1 maybe acts as a novel myocardial depressant factor during cardiac injury. 相似文献
873.
Juarez-Jimenez B Rodelas B Martinez-Toledo MV Gonzalez-Lopez J Crognale S Gallo AM Pesciaroli C Fenice M 《International journal of biological macromolecules》2008,43(1):27-31
Nineteen bacterial isolates were grown in shaken cultures in media containing chitin as carbon source and different additional nitrogen sources such as yeast nitrogen base (YNB), yeast extract (YE), corn steep liquor (CSL) and ammonium sulfate. Strain BM17 showed the highest activity (200 U/l) in medium containing Chitin (1%) and YNB (0.5%). Molecular analysis of the 16S rRNA gene showed that strain BM17 belongs to the species Paenibacillus pabuli (99.72% homology). The enzyme activity started after 12-24 h; exponential enzyme production was recorded from the 24th h and lasted till the 96th h of incubation when activity peaked to decrease thereafter. Medium optimisation was carried out by Response Surface Methodology (RSM) considering the effects of chitin, corn steep liquor and yeast extract. BM17 chitinolytic activity was induced by chitin but the increase of its concentration did not have significant effects on the enzyme activity. By contrast, the nitrogen source, particularly YE, strongly affected the enzyme production. 相似文献
874.
Lima PR Santos Wde J de Oliveira AB Goulart MO Kubota LT 《Biosensors & bioelectronics》2008,24(3):448-454
A simple and sensitive method for the electrocatalytic detection of NADH on a carbon paste electrode modified with a redox-active (NC)(2)C(6)H(3)-NO/(NC)(2)C(6)H(3)-NHOH (NOPH/NHOHPH) electrogenerated in situ from 4-nitrophthalonitrile (4-NPHN) is presented. The electrode modified with 4-NPHN showed an efficient electrocatalytic activity towards the oxidation of NADH with activation overpotential of 0.12V vs. Ag/AgCl. The formation of an intermediate charge transfer complex is proposed for the charge transfer reaction between NADH and the 4-NPHN-resulting system. The second-order rate constant for electrocatalytic oxidation of NADH, kappa(obs), and the apparent Michaelis-Menten constant K(M), at pH 7.0 were evaluated with rotating disk electrode (RDE) experiments, giving 1.0x10(4)mol(-1)Ls(-1) and 2.7x10(-5)molL(-1), respectively. Employing the Koutecky-Levich approach indicated that the NADH oxidation reaction involves two electrons. The sensor provided a linear response range for NADH from 0.8 up to 8.5mumolL(-1) with sensitivity, detection, quantification limits and time response of 0.50muALmumol(-1), 0.25mumolL(-1), 0.82mumolL(-1) and 0.1s, respectively. The repeatability of the measurements with the same sensor and different sensors, evaluated in terms of relative standard deviation, were 4.1 and 5.0%, respectively, for n=10. 相似文献
875.
Jones P Bottomley MJ Carfí A Cecchetti O Ferrigno F Lo Surdo P Ontoria JM Rowley M Scarpelli R Schultz-Fademrecht C Steinkühler C 《Bioorganic & medicinal chemistry letters》2008,18(11):3456-3461
The identification of class II HDAC inhibitors has been hampered by lack of efficient enzyme assays, in the preceding paper two assays have been developed to improve the efficiency of these enzymes: mutating an active site histidine to tyrosine, or by the use of a trifluoroacetamide lysine substrate, allowing screening to identify class II HDAC inhibitors. Herein, 2-trifluoroacetylthiophenes have been demonstrated to inhibit class II HDACs, resulting in the development of a series of 5-(trifluoroacetyl)thiophene-2-carboxamides as novel, potent and selective class II HDAC inhibitors. X-ray crystal structures of the HDAC 4 catalytic domain with a bound inhibitor demonstrate these compounds are active site inhibitors and bind in their hydrated form. 相似文献
876.
Mans BJ Andersen JF Francischetti IM Valenzuela JG Schwan TG Pham VM Garfield MK Hammer CH Ribeiro JM 《Insect biochemistry and molecular biology》2008,38(1):42-58
Ticks evolved various mechanisms to modulate their host's hemostatic and immune defenses. Differences in the anti-hemostatic repertoires suggest that hard and soft ticks evolved anti-hemostatic mechanisms independently, but raise questions on the conservation of salivary gland proteins in the ancestral tick lineage. To address this issue, the sialome (salivary gland secretory proteome) from the soft tick, Argas monolakensis, was determined by proteomic analysis and cDNA library construction of salivary glands from fed and unfed adult female ticks. The sialome is composed of approximately 130 secretory proteins of which the most abundant protein folds are the lipocalin, BTSP, BPTI and metalloprotease families which also comprise the most abundant proteins found in the salivary glands. Comparative analysis indicates that the major protein families are conserved in hard and soft ticks. Phylogenetic analysis shows, however, that most gene duplications are lineage specific, indicating that the protein families analyzed possibly evolved most of their functions after divergence of the two major tick families. In conclusion, the ancestral tick may have possessed a simple (few members for each family), but diverse (many different protein families) salivary gland protein domain repertoire. 相似文献
877.
Cuervo P Mesquita-Rodrigues C d'Avila Levy CM Britto C Pires FA Gredilha R Alves CR Jesus JB 《Memórias do Instituto Oswaldo Cruz》2008,103(5):504-506
We report for the first time the expression of multiple protease activities in the first instar larva (L1) of the flesh fly Oxysarcodexia thornax (Walker). Zymographic analysis of homogenates from freshly obtained L1 revealed a complex proteolytic profile ranging from 21.5 to 136 kDa. Although some activities were detected at pH 3.5 and 5.5, the optimum pH for most of the proteolytic activities was between pH 7.5 and 9.5. Seven of 10 proteases were completely inactivated by phenyl-methyl sulfonyl-fluoride, suggesting that main proteases expressed by L1 belong to serine proteases class. Complete inactivation of all enzymatic activities was obtained using N-p-Tosyl-L-phenylalanine chloromethyl ketone (100 microM), a specific inhibitor of chymotrypsin-like serine proteases. 相似文献
878.
Malancona S Colarusso S Ontoria JM Marchetti A Poma M Stansfield I Laufer R Di Marco A Taliani M Verdirame M Gonzalez-Paz O Matassa VG Narjes F 《Bioorganic & medicinal chemistry letters》2004,14(17):4575-4579
SAR on the phenethylamide 1 (Ki 1.2 microM) in the P2- and the P'-position led to potent inhibitors, one of which showed good exposure and low clearance when administered intramuscularly to rat. 相似文献
879.
Nizi E Koch U Ontoria JM Marchetti A Narjes F Malancona S Matassa VG Gardelli C 《Bioorganic & medicinal chemistry letters》2004,14(9):2151-2154
The N-terminal aminoacid of phenethylamide tripeptide inhibitors of the hepatitis C virus NS3 protease can be replaced with an alpha-hydroxy acid to obtain more 'drug like' inhibitors with low micromolar activity. The preferred S-configuration of the capping residue can be explained by molecular modeling studies. 相似文献
880.