全文获取类型
收费全文 | 380篇 |
免费 | 26篇 |
出版年
2023年 | 2篇 |
2022年 | 4篇 |
2021年 | 8篇 |
2020年 | 7篇 |
2019年 | 3篇 |
2018年 | 12篇 |
2017年 | 7篇 |
2016年 | 12篇 |
2015年 | 21篇 |
2014年 | 22篇 |
2013年 | 16篇 |
2012年 | 26篇 |
2011年 | 31篇 |
2010年 | 21篇 |
2009年 | 16篇 |
2008年 | 23篇 |
2007年 | 31篇 |
2006年 | 23篇 |
2005年 | 16篇 |
2004年 | 27篇 |
2003年 | 19篇 |
2002年 | 12篇 |
2001年 | 3篇 |
2000年 | 3篇 |
1999年 | 3篇 |
1998年 | 6篇 |
1997年 | 1篇 |
1996年 | 2篇 |
1995年 | 2篇 |
1994年 | 2篇 |
1993年 | 1篇 |
1991年 | 1篇 |
1990年 | 1篇 |
1989年 | 3篇 |
1988年 | 1篇 |
1987年 | 2篇 |
1986年 | 1篇 |
1985年 | 1篇 |
1984年 | 3篇 |
1983年 | 1篇 |
1982年 | 1篇 |
1981年 | 1篇 |
1980年 | 2篇 |
1979年 | 1篇 |
1973年 | 4篇 |
1966年 | 1篇 |
排序方式: 共有406条查询结果,搜索用时 31 毫秒
101.
Identification of preferred protein interactions by phage-display of the human Src homology-3 proteome 总被引:2,自引:0,他引:2
下载免费PDF全文
![点击此处可从《EMBO reports》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Kärkkäinen S Hiipakka M Wang JH Kleino I Vähä-Jaakkola M Renkema GH Liss M Wagner R Saksela K 《EMBO reports》2006,7(2):186-191
We have determined the human genome to contain 296 different Src homology-3 (SH3) domains and cloned them into a phage-display vector. This provided a powerful and unbiased system for simultaneous assaying of the complete human SH3 proteome for the strongest binding to target proteins of interest, without the limitations posed by short linear peptide ligands or confounding variables of more indirect methods for protein interaction screening. Studies involving three ligand proteins, human immunodeficiency virus-1 Nef, p21-activated kinase (PAK)2 and ADAM15, showed previously reported as well as novel SH3 partners with nanomolar affinities specific for them. This argues that SH3 domains may have a more dominant role in directing cellular protein interactions than has been assumed. Besides showing potentially important new SH3-directed interactions, these studies also led to the discovery of novel signalling proteins, such as the PAK2-binding adaptor protein POSH2 and the ADAM15-binding sorting nexin family member SNX30. 相似文献
102.
Concha ML Russell C Regan JC Tawk M Sidi S Gilmour DT Kapsimali M Sumoy L Goldstone K Amaya E Kimelman D Nicolson T Gründer S Gomperts M Clarke JD Wilson SW 《Neuron》2003,39(3):423-438
The mechanisms that establish behavioral, cognitive, and neuroanatomical asymmetries are poorly understood. In this study, we analyze the events that regulate development of asymmetric nuclei in the dorsal forebrain. The unilateral parapineal organ has a bilateral origin, and some parapineal precursors migrate across the midline to form this left-sided nucleus. The parapineal subsequently innervates the left habenula, which derives from ventral epithalamic cells adjacent to the parapineal precursors. Ablation of cells in the left ventral epithalamus can reverse laterality in wild-type embryos and impose the direction of CNS asymmetry in embryos in which laterality is usually randomized. Unilateral modulation of Nodal activity by Lefty1 can also impose the direction of CNS laterality in embryos with bilateral expression of Nodal pathway genes. From these data, we propose that laterality is determined by a competitive interaction between the left and right epithalamus and that Nodal signaling biases the outcome of this competition. 相似文献
103.
The vaccinia virus G1L putative metalloproteinase is essential for viral replication in vivo
下载免费PDF全文
![点击此处可从《Journal of virology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
The function of the putative metalloproteinase encoded by the vaccinia virus G1L gene is unknown. To address this question, we have generated a vaccinia virus strain in which expression of the G1L gene is dependent on the addition of tetracycline (TET) when infection proceeds in a cell line expressing the tetracycline repressor. The vvtetOG1L virus replicated similarly to wild-type Western Reserve (WR) virus in these cells when TET was present but was arrested at a late stage in viral maturation in the absence of TET. This arrest resulted in the accumulation of 98.5% round immature virus particles compared to 6.9% at a similar time point when TET was present. Likewise, the titer of infectious virus progeny decreased by 98.9% +/- 0.97% when the vvtetOG1L virus was propagated in the absence of TET. Mutant virus replication was partially rescued by plasmid-encoded G1L, but not by G1L containing an HXXEH motif mutated to RXXQR. Modeling of G1L revealed a predicted structural similarity to the alpha-subunit of Saccharomyces cerevisiae mitochondrial processing peptidase (alpha-MPP). The HXXEH motif of G1L perfectly overlaps the HXXDR motif of alpha-MPP in this model. These results demonstrate that G1L is essential for virus maturation and suggest that G1L is a metalloproteinase with structural homology to alpha-MPP. However, no obvious effects on the expression and processing of the vaccinia virus major core proteins were observed in the G1L conditional mutant in the absence of TET compared to results for the TET and wild-type WR controls, suggesting that G1L activity is required after this step in viral morphogenesis. 相似文献
104.
Kato N Sugiyama K Namba K Dansako H Nakamura T Takami M Naka K Nozaki A Shimotohno K 《Biochemical and biophysical research communications》2003,306(3):756-766
The hepatitis C virus (HCV) replicon system is a potent tool for understanding the mechanisms of HCV replication and proliferation, and for the development of treatments for patients with HCV. Recently, we established an HCV subgenomic replicon (50-1) using HCV genome RNA obtained from the cultured human T cell line MT-2C infected with HCV (isolate 1B-1) in vitro. In order to further obtain other HCV replicons without difficulty, we generated a replicon RNA library derived from human non-neoplastic hepatocytes infected with HCV (isolate 1B-2) in vitro. Upon transfection of the generated RNA library to "cured cells," from which the 50-1 subgenomic replicon was eliminated by prolonged treatment with interferon-alpha, we successfully established a new HCV subgenomic replicon, 1B-2R1. We characterized 1B-2R1 replicon in terms of efficiency of replication, HCV sequence, and sensitivity to interferons. The results revealed that the replication level of the 1B-2R1 replicon was comparable to that of the 50-1 replicon. We also found that the 1B-2R1 replicon possessed an HCV sequence distinct from those of other replicons established to date, and that the 1B-2R1 replicon was sensitive to interferon-alpha, interferon-beta, and interferon-gamma. Taken together, present results indicate that the replicon RNA library generated using an in vitro HCV infection system is useful for the establishment of an HCV subgenomic replicon. 相似文献
105.
PML-RARA-targeted DNA vaccine induces protective immunity in a mouse model of leukemia 总被引:12,自引:0,他引:12
Padua RA Larghero J Robin M le Pogam C Schlageter MH Muszlak S Fric J West R Rousselot P Phan TH Mudde L Teisserenc H Carpentier AF Kogan S Degos L Pla M Bishop JM Stevenson F Charron D Chomienne C 《Nature medicine》2003,9(11):1413-1417
Despite improved molecular characterization of malignancies and development of targeted therapies, acute leukemia is not curable and few patients survive more than 10 years after diagnosis. Recently, combinations of different therapeutic strategies (based on mechanisms of apoptosis, differentiation and cytotoxicity) have significantly increased survival. To further improve outcome, we studied the potential efficacy of boosting the patient's immune response using specific immunotherapy. In an animal model of acute promyelocytic leukemia, we developed a DNA-based vaccine by fusing the human promyelocytic leukemia-retinoic acid receptor-alpha (PML-RARA) oncogene to tetanus fragment C (FrC) sequences. We show for the first time that a DNA vaccine specifically targeted to an oncoprotein can have a pronounced effect on survival, both alone and when combined with all-trans retinoic acid (ATRA). The survival advantage is concomitant with time-dependent antibody production and an increase in interferon-gamma (IFN-gamma). We also show that ATRA therapy on its own triggers an immune response in this model. When DNA vaccination and conventional ATRA therapy are combined, they induce protective immune responses against leukemia progression in mice and may provide a new approach to improve clinical outcome in human leukemia. 相似文献
106.
Mannerström M Tähti H Tiihonen K Salama A 《Comparative biochemistry and physiology. Part A, Molecular & integrative physiology》2003,136(3):779-790
The transport of D-glucose into rainbow trout (Oncorhynchus mykiss) and river lamprey (Lampetra fluviatilis) hepatocytes, as well as into rainbow trout hepatoblastoma cell line RTH-149 was studied using tracer methods. The half-time for D-glucose equilibration was 15 s for rainbow trout. The half-times for the non-metabolizable D-glucose analog, 3-O-methyl-D-glucose equilibration were 8 s, 37 s and 38 s for rainbow trout, lamprey and RTH-149 cells, respectively. The 3-O-methyl-D-glucose was taken up by rainbow trout hepatocytes by facilitated diffusion in addition to simple diffusion. The uptake showed saturation kinetics with the K(m) of 37 mM and V(max) of 62 mmol kg(-1) cells min(-1). The uptake was sensitive to phloretin and cytochalasin B, but not affected by ouabain. The 3-O-methyl-D-glucose uptake by lamprey hepatocytes and RTH-149 cells showed no indication of saturation up to 160 mM, and was not affected by phloretin, cytochalasin B or ouabain, which suggests the mode of transport to be by passive diffusion. However, immunocytochemical stainings revealed the existence of mammalian type GLUT1 and GLUT2 transporters in all cells studied. The lack of a functioning carrier-mediated glucose uptake in lamprey hepatocytes might be due to its physiological state (prespawning starvation). The minor 3-O-methyl-D-glucose uptake into RTH-149 cells compared to freshly isolated rainbow trout hepatocytes might reflect low metabolic activity of the cell lines. Under the conditions applied the RTH-149 cell line is no suitable in vitro model for glucose transport in fish cells. 相似文献
107.
Abnormal lymphatic vessel development in neuropilin 2 mutant mice 总被引:40,自引:0,他引:40
Yuan L Moyon D Pardanaud L Bréant C Karkkainen MJ Alitalo K Eichmann A 《Development (Cambridge, England)》2002,129(20):4797-4806
Neuropilin 2 is a receptor for class III semaphorins and for certain members of the vascular endothelial growth factor family. Targeted inactivation of the neuropilin 2 gene (Nrp2) has previously shown its role in neural development. We report that neuropilin 2 expression in the vascular system is restricted to veins and lymphatic vessels. Homozygous Nrp2 mutants show absence or severe reduction of small lymphatic vessels and capillaries during development. This correlated with a reduction of DNA synthesis in the lymphatic endothelial cells of the mutants. Arteries, veins and larger, collecting lymphatic vessels developed normally, suggesting that neuropilin 2 is selectively required for the formation of small lymphatic vessels and capillaries. 相似文献
108.
A B10.S(7R) anti-B10.S(9R) serum (anti-IJE
k
C
d
) contained, as expected, antibodies specific for the I-E-subregion-encoded determinant Ia.7. However, tests on recombinant haplotypes demonstrated a series of unexpected weak extrareactions which could be interpreted to be directed against antigenic determinants encoded in the I-A subregion of the H-2 complex. The same type of extrareaction was observed in eluates from I-A
s
, I-E
k
cells coated with A.TH anti-A.TL (I-A
s
, I-E
s
anti-I-A
k
, I-E
k
) serum. This reactivity in serum and eluates could be interpreted as cross-reactivity between products of the I-E and I-A subregions. 相似文献
109.
Tetsuo Kunieda Michiko Nakagiri Marika Takami Hanako Ide Hiroyuki Ogawa 《Mammalian genome》1999,10(12):1146-1149
An inheritable bleeding disorder with light coat color caused by an autosomal recessive gene has been reported in a population
of Japanese black cattle. The disease has been diagnosed as Chediak-Higashi Syndrome (CHS) of cattle which correspond to a
human inheritable disorder caused by mutation in LYST gene. To characterize the molecular lesion causing CHS in cattle, cDNAs
encoding bovine LYST were isolated from a bovine brain cDNA library. The nucleotide and deduced amino acid sequences of bovine LYST had 89.6 and
90.2% identity with those of the human LYST gene, respectively. In order to identify the mutation within the LYST gene causing CHS in cattle, cDNA fragments of the LYST gene were amplified from an affected animal by RT-PCR and their nucleotide sequences were completely determined. Notably,
a nucleotide substitution of A to G transition, resulting in an amino acid substitution of histidine to arginine (H2015R)
was identified in the affected animal. The presence of the substitution was completely corresponding with the occurrence of
the CHS phenotype among 105 members of pedigrees of the Japanese black cattle and no cattle of other populations had this
substitution. These findings strongly suggested that H2015R is the causative mutation in CHS of Japanese black cattle.
Received: 25 May 1999 / Accepted: 26 July 1999 相似文献
110.
Cecilia Bonnet Jan Rusz Marika Megrelishvili Tomá? Sieger Olga Matou?ková Michael Okujava Hana Bro?ová Tomá? Nikolai Jaromír Hanu?ka Mariam Kapianidze Nina Mikeladze Nazi Botchorishvili Irine Khatiashvili Marina Janelidze Tereza Serranová Ond?ej Fiala Jan Roth Jonas Bergquist Robert Jech Sophie Rivaud-Péchoux Bertrand Gaymard Ev?en R??i?ka 《PloS one》2014,9(8)
Patients with ephedrone parkinsonism (EP) show a complex, rapidly progressive, irreversible, and levodopa non-responsive parkinsonian and dystonic syndrome due to manganese intoxication. Eye movements may help to differentiate parkinsonian syndromes providing insights into which brain networks are affected in the underlying disease, but they have never been systematically studied in EP. Horizontal and vertical eye movements were recorded in 28 EP and compared to 21 Parkinson''s disease (PD) patients, and 27 age- and gender-matched healthy subjects using standardized oculomotor tasks with infrared videooculography. EP patients showed slow and hypometric horizontal saccades, an increased occurrence of square wave jerks, long latencies of vertical antisaccades, a high error rate in the horizontal antisaccade task, and made more errors than controls when pro- and antisaccades were mixed. Based on oculomotor performance, a direct differentiation between EP and PD was possible only by the velocity of horizontal saccades. All remaining metrics were similar between both patient groups. EP patients present extensive oculomotor disturbances probably due to manganese-induced damage to the basal ganglia, reflecting their role in oculomotor system. 相似文献