全文获取类型
收费全文 | 910篇 |
免费 | 63篇 |
出版年
2021年 | 10篇 |
2019年 | 7篇 |
2018年 | 11篇 |
2017年 | 10篇 |
2016年 | 13篇 |
2015年 | 31篇 |
2014年 | 32篇 |
2013年 | 39篇 |
2012年 | 58篇 |
2011年 | 56篇 |
2010年 | 37篇 |
2009年 | 30篇 |
2008年 | 35篇 |
2007年 | 35篇 |
2006年 | 28篇 |
2005年 | 37篇 |
2004年 | 40篇 |
2003年 | 28篇 |
2002年 | 24篇 |
2001年 | 20篇 |
2000年 | 19篇 |
1999年 | 15篇 |
1998年 | 9篇 |
1997年 | 7篇 |
1996年 | 6篇 |
1995年 | 14篇 |
1994年 | 7篇 |
1992年 | 14篇 |
1991年 | 18篇 |
1990年 | 14篇 |
1989年 | 17篇 |
1988年 | 16篇 |
1987年 | 25篇 |
1986年 | 26篇 |
1985年 | 11篇 |
1984年 | 10篇 |
1982年 | 8篇 |
1981年 | 6篇 |
1980年 | 7篇 |
1979年 | 14篇 |
1978年 | 15篇 |
1977年 | 13篇 |
1976年 | 8篇 |
1975年 | 6篇 |
1974年 | 11篇 |
1973年 | 12篇 |
1972年 | 6篇 |
1971年 | 6篇 |
1967年 | 6篇 |
1962年 | 5篇 |
排序方式: 共有973条查询结果,搜索用时 15 毫秒
91.
Das B Rudra S Yadav A Ray A Rao AV Srinivas AS Soni A Saini S Shukla S Pandya M Bhateja P Malhotra S Mathur T Arora SK Rattan A Mehta A 《Bioorganic & medicinal chemistry letters》2005,15(19):4261-4267
Novel oxazolidinones were synthesized containing a number of substituted five-membered heterocycles attached to the 'piperazinyl-phenyl-oxazolidinone' core of eperezolid. Further, the piperazine ring of the core was replaced by other diamino-heterocycles. These modifications led to several compounds with potent activity against a spectrum of resistant and susceptible gram-positive organisms, along with the identification of ranbezolid (RBx 7644) as a clinical candidate. 相似文献
92.
Open-channel block by the cytoplasmic tail of sodium channel beta4 as a mechanism for resurgent sodium current 总被引:1,自引:0,他引:1
Voltage-gated sodium channels with "resurgent" kinetics are specialized for high-frequency firing. The alpha subunits interact with a blocking protein that binds open channels upon depolarization and unbinds upon repolarization, producing resurgent sodium current. By limiting classical inactivation, the cycle of block and unblock shortens refractory periods. To characterize the blocker in Purkinje neurons, we briefly exposed inside-out patches to substrate-specific proteases. Trypsin and chymotrypsin each removed resurgent current, consistent with established roles for positively charged and hydrophobic/aromatic groups in blocking sodium channels. In Purkinje cells, the only known sodium channel-associated subunit that has a cytoplasmic sequence with several positive charges and clustered hydrophobic/aromatic residues is beta4 (KKLITFILKKTREK; beta4(154-167)). After enzymatic removal of block, beta4(154-167) fully reconstituted resurgent current, whereas scrambled or point-mutated peptides were ineffective. In CA3 pyramidal neurons, which lack beta4 and endogenous block, beta4(154-167) generated resurgent current. Thus, beta4 may be the endogenous open-channel blocker responsible for resurgent kinetics. 相似文献
93.
Conclusions In vivo ocular availability of ketorolac was evaluated following ocular instillation of aqueous, oil, and ointment formulations
to normal corneas of rabbits and monitoring ketorolac concentration in aqueous humor by HPLC. Compared with aqueous drop,
sesame and soybean oil drops of ketorolac provided higher ocular availability followed by ophthalmic ointment. The ointment
formulation provided maximum sustained effect. Ketorolac aqueous drop with BAC and EDTA improved the rate of ocular absorption
though not the extent.
Published: October 24, 2005 相似文献
94.
95.
PKCeta is required for beta1gamma2/beta3gamma2- and PKD-mediated transport to the cell surface and the organization of the Golgi apparatus 下载免费PDF全文
Protein kinase D (PKD) binds to a pool of diacylglycerol (DAG) in the TGN and undergoes a process of activation that involves heterotrimeric GTP-binding protein subunits betagamma to regulate membrane fission. This fission reaction is used to generate transport carriers at the TGN that are en route to the cell surface. We now report that PKD is activated specifically by G protein subunit beta1gamma2 and beta3gamma2 via the Golgi apparatus-associated PKCeta. Compromising the kinase activity of PKCeta-inhibited protein transport from TGN to the cell surface. Expression of constitutively activated PKCeta caused Golgi fragmentation, which was inhibited by a kinase inactive form of PKD. Our findings reveal that betagamma, PKCeta, and PKD act in series to generate transport carriers from the TGN and their overactivation results in complete vesiculation of the Golgi apparatus. 相似文献
96.
97.
CELF6, a member of the CELF family of RNA-binding proteins, regulates muscle-specific splicing enhancer-dependent alternative splicing 总被引:5,自引:0,他引:5
Ladd AN Nguyen NH Malhotra K Cooper TA 《The Journal of biological chemistry》2004,279(17):17756-17764
We previously described a family of five RNA-binding proteins: CUG-binding protein, embryonic lethal abnormal vision-type RNA-binding protein 3, and the CUG-binding protein and embryonic lethal abnormal vision-type RNA-binding protein 3-like factors (CELFs) 3, 4, and 5. We demonstrated that all five of these proteins specifically activate exon inclusion of cardiac troponin T minigenes in vivo via muscle-specific splicing enhancer (MSE) sequences. We also predicted that a sixth family member, CELF6, was located on chromosome 15. Here, we describe the isolation and characterization of CELF6. Like the previously described CELF proteins, CELF6 shares a domain structure containing three RNA-binding domains and a divergent domain of unknown function. CELF6 is strongly expressed in kidney, brain, and testis and is expressed at very low levels in most other tissues. In the brain, expression is widespread and maintained from the fetus to the adult. CELF6 activates exon inclusion of a cardiac troponin T minigene in transient transfection assays in an MSE-dependent manner and can activate inclusion via multiple copies of a single element, MSE2. These results place CELF6 in a functional subfamily of CELF proteins that includes CELFs 3, 4, and 5. CELF6 also promotes skipping of exon 11 of insulin receptor, a known target of CELF activity that is expressed in kidney. 相似文献
98.
Funke B Finn CT Plocik AM Lake S DeRosse P Kane JM Kucherlapati R Malhotra AK 《American journal of human genetics》2004,75(5):891-898
Linkage and association studies have recently implicated dystrobrevin-binding protein 1 (DTNBP1) in the etiology of schizophrenia. We analyzed seven previously tested DTNBP1 single-nucleotide polymorphisms (SNPs) in a cohort of 524 individuals with schizophrenia or schizoaffective disorder and 573 control subjects. The minor alleles of three SNPs (P1578, P1763, and P1765) were positively associated with the diagnosis of schizophrenia or schizoaffective disorder in the white subset of the study cohort (258 cases, 467 controls), with P1578 showing the most significant association (odds ratio 1.76, P =.0026). The same three SNPs were also associated in a smaller Hispanic subset (51 cases, 32 controls). No association was observed in the African American subset (215 cases, 74 controls). A stratified analysis of the white and Hispanic subsets showed association with the minor alleles of four SNPs (P1578, P1763, P1320, and P1765). Again, the most significant association was observed for P1578 (P =.0006). Haplotype analysis supported these findings, with a single risk haplotype significantly overrepresented in the white sample (P =.005). Our study provides further evidence for a role of the DTNBP1 gene in the genetic etiology of schizophrenia. 相似文献
99.
Kumar A Dasaradhi PV Chauhan VS Malhotra P 《Biochemical and biophysical research communications》2004,317(1):38-45
Falcipain-2 is one of the principal hemoglobinases of Plasmodium falciparum, a human malaria parasite. It has a typical papain family cysteine protease structural organization, a large pro-domain, a mature domain with conserved active site amino acids. Pro-domain of falcipain-2 also contains two important conserved motifs, "GNFD" and "ERFNIN." The "GNFD" motif has been shown to be responsible for correct folding and stability in case of many papain family proteases. In the present study, we carried out site-directed mutagenesis to assess the roles of active site residues and pro-domain residues for the activity of falcipain-2. Our results showed that substitutions of putative active site residues; Q36, C42, H174, and N204 resulted in complete loss of falcipain-2 activity, while W206 and D155 mutants retained partial/complete activity in comparison to the wild type falcipain-2. Homology modeling data also corroborate the results of mutagenesis; Q36, C42, H174, N204, and W206 residues form the active site loop of the enzyme and D155 lie outside the active pocket. Substitutions in the pro-region did not affect the activity of falcipain-2. This implies that falcipain-2 shares active site residues with other members of papain family, however pro-region of falcipain-2 does not play any role in the activity of enzyme. 相似文献
100.
Gianni Guizzunti Thomas P. Brady Derek Fischer Vivek Malhotra Emmanuel A. Theodorakis 《Bioorganic & medicinal chemistry》2010,18(6):2115-2122
The cellular activity of norrisolide (7), a novel Golgi-vesiculating agent, was dissected as function of its chemical structure. This natural product induces irreversible vesiculation of the Golgi membranes and blocks protein transport at the level of the Golgi. The Golgi localization and fragmentation effects of 7 depend on the presence of the perhydroindane core, while the irreversibility of fragmentation depends on the acetyl group of 7. We show that fluorescent derivatives of norrisolide are able to localize to the Golgi apparatus and represent important tools for the study of the Golgi structure and function. 相似文献