全文获取类型
收费全文 | 5073篇 |
免费 | 362篇 |
国内免费 | 5篇 |
出版年
2023年 | 16篇 |
2022年 | 27篇 |
2021年 | 65篇 |
2020年 | 27篇 |
2019年 | 58篇 |
2018年 | 63篇 |
2017年 | 69篇 |
2016年 | 107篇 |
2015年 | 161篇 |
2014年 | 177篇 |
2013年 | 324篇 |
2012年 | 329篇 |
2011年 | 346篇 |
2010年 | 166篇 |
2009年 | 181篇 |
2008年 | 335篇 |
2007年 | 301篇 |
2006年 | 317篇 |
2005年 | 308篇 |
2004年 | 318篇 |
2003年 | 284篇 |
2002年 | 263篇 |
2001年 | 91篇 |
2000年 | 67篇 |
1999年 | 93篇 |
1998年 | 70篇 |
1997年 | 53篇 |
1996年 | 50篇 |
1995年 | 58篇 |
1994年 | 54篇 |
1993年 | 49篇 |
1992年 | 55篇 |
1991年 | 42篇 |
1990年 | 58篇 |
1989年 | 53篇 |
1988年 | 48篇 |
1987年 | 38篇 |
1986年 | 31篇 |
1985年 | 56篇 |
1984年 | 38篇 |
1983年 | 27篇 |
1982年 | 25篇 |
1981年 | 13篇 |
1980年 | 18篇 |
1979年 | 14篇 |
1978年 | 17篇 |
1977年 | 10篇 |
1976年 | 11篇 |
1973年 | 11篇 |
1972年 | 9篇 |
排序方式: 共有5440条查询结果,搜索用时 15 毫秒
141.
Shahid N. Khan John D. Persons Michel Guerrero Tatiana V. Ilina Masayuki Oda Rieko Ishima 《Protein science : a publication of the Protein Society》2021,30(3):571
A clinically‐relevant, drug‐resistant mutant of HIV‐1 protease (PR), termed Flap+(I54V) and containing L10I, G48V, I54V and V82A mutations, is known to produce significant changes in the entropy and enthalpy balance of drug‐PR interactions, compared to wild‐type PR. A similar mutant, Flap+(I54A), which evolves from Flap+(I54V) and contains the single change at residue 54 relative to Flap+(I54V), does not. Yet, how Flap+(I54A) behaves in solution is not known. To understand the molecular basis of V54A evolution, we compared nuclear magnetic resonance (NMR) spectroscopy, fluorescence spectroscopy, isothermal titration calorimetry, and enzymatic assay data from four PR proteins: PR (pWT), Flap+(I54V), Flap+(I54A), and Flap+(I54), a control mutant that contains only L10I, G48V and V82A mutations. Our data consistently show that selection to the smaller side chain at residue 54, not only decreases inhibitor affinity, but also restores the catalytic activity. 相似文献
142.
Sakiyama Tomoki Morimoto Junko Matsubayashi Jun Furukawa Yasuto Kondo Mami Tsuruga Hifumi Mano Tsutomu Nakamura Futoshi 《Landscape and Ecological Engineering》2021,17(3):351-362
Landscape and Ecological Engineering - Investigating factors underlying human-wildlife conflicts in agricultural landscapes is important for both preventing crop damage and wildlife conservation.... 相似文献
143.
Takafumi Watanabe Hideaki Nanamiya Manabu Kojima Shinji Nomura Shigenori Furukawa Shu Soeda Daisuke Tanaka Takao Isogai Jun-ichi Imai Shinya Watanabe Keiya Fujimori 《Translational oncology》2021,14(3):101010
PurposeEndometrial carcinoma (EC) is a clinically heterogeneous disease characterized by a number of different histological subtypes, and its heterogeneity may be involved in the accumulation of multiple genetic alterations. The aim of this work was to investigate the comprehensive mutational profile of EC tumors, and examine the associations between somatic mutations and clinicopathological features or survival in EC patients.MethodsA total of 100 surgical tumors were obtained from EC patients who had previously undergone surgery. Genomic DNA samples extracted from fresh-frozen tissues were analyzed using the Ion AmpliSeq Cancer Hotspot Panel v2 Kit, covering 50 tumor-related genes.ResultsValidated mutations were detected in 91 of the 100 tumors (91%) and identified in eight of the most frequently mutated genes, namely PTEN (57%), PIK3CA (51%), TP53 (30%), KRAS (23%), CTNNB1 (21%), FBFR2 (13%), FBXW7(10%) and RB1 (9%). PTEN mutations were found to associated with young age (< 60), early-stage, endometrioid histology, non-recurrence and better overall survival (OS). CTNNB1 mutations were associated with young age, endometrioid histology and better OS. On the other hands, TP53 mutations were associated with late-stage, non-endometrioid histology, high-grade, recurrence and worse OS. FBWX7 mutations were associated with late-stage, vascular invasion and lymph node metastasis. FGFR2 mutations correlated with deep (≥ 1/2) myometrial invasion.ConclusionOur comprehensive mutational profile will be useful for understanding and evaluating the molecular characteristics of EC tumors, and may lead to the establishment of novel treatment strategies that improve the survival of patients with EC in the future. 相似文献
144.
145.
Graham H. Diering Yuka Numata Steven Fan John Church Masayuki Numata 《Molecular biology of the cell》2013,24(21):3435-3448
To facilitate polarized vesicular trafficking and signal transduction, neuronal endosomes have evolved sophisticated mechanisms for pH homeostasis. NHE5 is a member of the Na+/H+ exchanger family and is abundantly expressed in neurons and associates with recycling endosomes. Here we show that NHE5 potently acidifies recycling endosomes in PC12 cells. NHE5 depletion by plasmid-based short hairpin RNA significantly reduces cell surface abundance of TrkA, an effect similar to that observed after treatment with the V-ATPase inhibitor bafilomycin. A series of cell-surface biotinylation experiments suggests that anterograde trafficking of TrkA from recycling endosomes to plasma membrane is the likeliest target affected by NHE5 depletion. NHE5 knockdown reduces phosphorylation of Akt and Erk1/2 and impairs neurite outgrowth in response to nerve growth factor (NGF) treatment. Of interest, although both phosphoinositide 3-kinase–Akt and Erk signaling are activated by NGF-TrkA, NGF-induced Akt-phosphorylation appears to be more sensitively affected by perturbed endosomal pH. Furthermore, NHE5 depletion in rat cortical neurons in primary culture also inhibits neurite formation. These results collectively suggest that endosomal pH modulates trafficking of Trk-family receptor tyrosine kinases, neurotrophin signaling, and possibly neuronal differentiation. 相似文献
146.
Nobuho Tanaka Yasuko Ikeda Tetsuo Yamaguchi Hiroshi Furukawa Hiroyuki Mitomi Takumi Nakagawa Shigeto Tohma Naoshi Fukui 《Arthritis research & therapy》2013,15(5):R127
Introduction
Articular chondrocytes undergo an obvious phenotypic change when cultured in monolayers. During this change, or dedifferentiation, the expression of type I and type III procollagen is induced where normal chondrocytes express little type I and type III procollagen. In this study, we attempted to determine the mechanism(s) for the induction of such procollagen expression in dedifferentiating chondrocytes.Methods
All experiments were performed using primary-cultured human articular chondrocytes under approval of institutional review boards. Integrin(s) responsible for the induction of type I and type III procollagen expression were specified by RNAi experiments. The signal pathway(s) involved in the induction were determined by specific inhibitors and RNAi experiments. Adenovirus-mediated experiments were performed to identify a small GTPase regulating the activity of integrins in dedifferentiating chondrocytes. The effect of inhibition of integrins on dedifferentiation was investigated by experiments using echistatin, a potent disintegrin. The effect of echistatin was investigated first with monolayer-cultured chondrocytes, and then with pellet-cultured chondrocytes.Results
In dedifferentiating chondrocytes, α5β1 integrin was found to be involved in the induction of type I and type III procollagen expression. The induction was known to be mediated by v-akt murine thymoma viral oncogene homolog (AKT) signaling. Among the three AKT isoforms, AKT1 seemed to be most involved in the signaling. Elated RAS viral (r-ras) oncogene homolog (RRAS) was considered to regulate the progression of dedifferentiation by modulating the affinity and avidity of α5β1 integrin to ligands. Echistatin inhibited dedifferentiation of monolayer-cultured chondrocytes. Furthermore, the matrix formed by pellet-cultured chondrocytes more closely resembled that of normal cartilage compared with the controls.Conclusions
The result of this study has shown, for the first time, that α5β1 integrin may be responsible for the induction of non-cartilaginous collagen expression in chondrocytes undergoing dedifferentiation. Again, this study has shown that the inhibition of ligand ligation to integrins may be an effective strategy to inhibit phenotypic change of cultured chondrocytes, and to improve the quality of matrix synthesized by primary cultured chondrocytes. 相似文献147.
Hiroaki Ozaki Yoshinori Ogawa Masayuki Mine Hiroaki Sawai 《Nucleosides, nucleotides & nucleic acids》2013,32(5):911-923
Abstract Acridine-modified oligodeoxyribonucleotides (ODNs) at the C5-position of a 2′-deoxyuridine via different lengths of linker arms were synthesized. Reaction of 5-(N-aminoalkyl)carbamoylmethyl-2′-deoxyuridines with 9-phenoxyacridine gave the acridine-modified 2′-deoxyuridines which were incorporated into ODNs. The duplexes containing the acridine-modified strands and their complementary DNA or RNA were thermally more stable than that containing the unmodified strand. Thermal stability of the duplexes of the modified ODNs varied depending on the length of the linker arms. 相似文献
148.
Hideo Inoue Masaki Shimizu Takako Furukawa Takashi Tamura Miwa Matsui Eiko Ohtsuka 《Nucleosides, nucleotides & nucleic acids》2013,32(6-7):1503-1505
Abstract 2′-Deoxy- and 2′-O-methyl-5′-O-terpyridyl derivatives of adenosine and cytidine were synthesized and used to construct 5′-end-modified oligonucleotides. These antisense agents complexed with Cu(II) exclusively cleaved a complementary RNA oligomer at the site opposite the terpyridine-nucleoside residue. We also found that the terpyridine·Cu(II) moiety stabilizes 2′-O-methyl RNA duplex. These suggest that after RNA hybridization, the terpyridine moiety is close to the RNA strand, presumably in an end capping manner. 相似文献
149.
Yukio Kitade Masaharu Wakana Shin-ichi Terai Takayuki Tsuboi Masayuki Nakanishi Chizuko Yatome 《Nucleosides, nucleotides & nucleic acids》2013,32(12):2323-2333
Abstract 2-Bromoadenosine-substituted analogues of 2–5A, p5′A2′p-5′A2′p5′(br2A), p5′(br2A)2′p5′A2′p5′A, and p5′(br2A)2′p5′(br2A)2′p-S′(br2A), were prepared via a modification of a lead ion-catalyzed ligation reaction and were subsequently converted into the corresponding 5′-triphosphates. Both binding and activation of human recombinant RNase L by various 2-bromoadenosine-substituted 2–5A analogues were examined. Among the 2-bromoadenosine-substituted 2–5A analogues, the analogue with 2-bromoadenosine residing in the 2′-terminal position, p5′A2′p5′A2′p-5′(br2A), showed the strongest binding affinity and was as effective as 2–5A itself as an activator of RNase L. The CD spectrum of p5′A2′p-5′A2′p5′(br2A) was superimposable on that of p5′A2′p5′A2′p5′A, indicative of an anti orientation about the base-glycoside bonds as in naturally occurring 2–5A. 相似文献
150.
Hiroshi Shiragami Yusuke Amino Yutaka Honda Masayuki Arai Yasuhiro Tanaka Hisao Iwagami 《Nucleosides, nucleotides & nucleic acids》2013,32(1-3):31-45
Abstract Practical method to produce 2′,3′-dideoxypurinenucleosides from 9-(2,5-di-O-acetyl-3-bromo-3-deoxy-β-D-xylofuranosyl)purines (1) was developed. High ratio of 2′,3′-dideoxynucleoside to 3′-deoxyribonucleoside was obtained by selecting the reaction conditions (solvent, pH and/or base), or changing 2′-acyloxy leaving group. The reaction mechanism was studied by deuteration experiments of 1a and 1-(3,5-di-O-acety1-2-bromo-2-deoxy-β-D-ribofuranosyl)thymine (12). 相似文献