全文获取类型
收费全文 | 3499篇 |
免费 | 296篇 |
国内免费 | 8篇 |
出版年
2023年 | 20篇 |
2022年 | 19篇 |
2021年 | 50篇 |
2020年 | 36篇 |
2019年 | 46篇 |
2018年 | 68篇 |
2017年 | 46篇 |
2016年 | 101篇 |
2015年 | 152篇 |
2014年 | 196篇 |
2013年 | 222篇 |
2012年 | 302篇 |
2011年 | 269篇 |
2010年 | 148篇 |
2009年 | 156篇 |
2008年 | 200篇 |
2007年 | 182篇 |
2006年 | 155篇 |
2005年 | 139篇 |
2004年 | 139篇 |
2003年 | 131篇 |
2002年 | 126篇 |
2001年 | 104篇 |
2000年 | 61篇 |
1999年 | 89篇 |
1998年 | 29篇 |
1997年 | 26篇 |
1996年 | 23篇 |
1995年 | 22篇 |
1994年 | 24篇 |
1993年 | 20篇 |
1992年 | 50篇 |
1991年 | 33篇 |
1990年 | 39篇 |
1989年 | 32篇 |
1988年 | 40篇 |
1987年 | 34篇 |
1986年 | 35篇 |
1985年 | 23篇 |
1984年 | 14篇 |
1983年 | 14篇 |
1981年 | 13篇 |
1980年 | 12篇 |
1979年 | 26篇 |
1978年 | 13篇 |
1977年 | 11篇 |
1976年 | 14篇 |
1975年 | 12篇 |
1974年 | 19篇 |
1972年 | 12篇 |
排序方式: 共有3803条查询结果,搜索用时 15 毫秒
121.
HER2 is overexpressed in 15–20% of breast cancers. HER2 overexpression is known to reduce apoptosis but the underlying mechanisms for this association remain unclear. To elucidate the mechanisms for HER2-mediated survival, we investigated the relationship between HER2 and p53 upregulated modulator of apoptosis (PUMA), a potent apoptosis inducer. Our results showed that HER2 interacts with PUMA, which was independent of HER2 activation. In addition, we observed that HER2 interacted with PUMA in both mitochondrial and non-mitochondrial compartments. We next examined whether HER2 phosphorylates PUMA. Notably, PUMA tyrosine phosphorylation has never been reported. Using an intracellular assay, we found PUMA to be phosphorylated in breast cancer cells with activated HER2. Via cell-free HER2 kinase assay, we observed that PUMA was directly phosphorylated by HER2. Activation of HER2 decreased PUMA protein half-life. To identify which of the three tyrosines within PUMA are targeted by HER2, we generated three PUMA non-phosphorylation mutants each with a single Tyr→Phe substitution. Results indicated that each PUMA single mutant had lost some, but not all phosphorylation by HER2 indicating that HER2 targets all three tyrosines. Consequently, we created an additional PUMA mutant with all three tyrosines mutated (TM-PUMA) that could not be phosphorylated by HER2. Importantly, TM-PUMA was found to have a longer half-life than PUMA. An inverse association was observed between HER2 and PUMA in 93 invasive breast carcinoma samples. We further found that TM-PUMA suppressed growth of breast cancer cells to a greater degree than PUMA. Also, TM-PUMA had a stronger propensity to induce apoptosis than PUMA. Together, our results demonstrate, for the first time, that PUMA can be tyrosine phosphorylated and that HER2-mediated phosphorylation destabilizes PUMA protein. The HER2-PUMA interplay represents a novel mechanism by which PUMA is regulated and a new molecular basis for HER2-mediated growth and survival of cancer cells. 相似文献
122.
Metamodelling a 3D architectural root-system model to provide a simple model based on key processes and species functional groups 总被引:1,自引:0,他引:1
Pagès Loïc Pointurier Olivia Moreau Delphine Voisin Anne-Sophie Colbach Nathalie 《Plant and Soil》2020,448(1-2):231-251
Plant and Soil - The architecture of root systems determines where and how much resources plants can extract from the soil, how they compete for soil resources, and how they interact with soil... 相似文献
123.
Yuan Zhang Yang Chen Chenran Wang Chun-Chao Lo Xiuwen Liu Wei Wu Jinfeng Zhang 《Proteins》2020,88(7):819-829
Designing protein sequences that fold to a given three-dimensional (3D) structure has long been a challenging problem in computational structural biology with significant theoretical and practical implications. In this study, we first formulated this problem as predicting the residue type given the 3D structural environment around the C α atom of a residue, which is repeated for each residue of a protein. We designed a nine-layer 3D deep convolutional neural network (CNN) that takes as input a gridded box with the atomic coordinates and types around a residue. Several CNN layers were designed to capture structure information at different scales, such as bond lengths, bond angles, torsion angles, and secondary structures. Trained on a very large number of protein structures, the method, called ProDCoNN (protein design with CNN), achieved state-of-the-art performance when tested on large numbers of test proteins and benchmark datasets. 相似文献
124.
Sara Chiarella Antonella De Cola Giovanni Luca Scaglione Erminia Carletti Vincenzo Graziano Daniela Barcaroli Carlo Lo Sterzo Adele Di Matteo Carmine Di Ilio Brunangelo Falini Alessandro Arcovito Vincenzo De Laurenzi Luca Federici 《Nucleic acids research》2013,41(5):3228-3239
Nucleophosmin (NPM1) is an abundant nucleolar protein implicated in ribosome maturation and export, centrosome duplication and response to stress stimuli. NPM1 is the most frequently mutated gene in acute myeloid leukemia. Mutations at the C-terminal domain led to variant proteins that aberrantly and stably translocate to the cytoplasm. We have previously shown that NPM1 C-terminal domain binds with high affinity G-quadruplex DNA. Here, we investigate the structural determinants of NPM1 nucleolar localization. We show that NPM1 interacts with several G-quadruplex regions found in ribosomal DNA, both in vitro and in vivo. Furthermore, the most common leukemic NPM1 variant completely loses this activity. This is the consequence of G-quadruplex–binding domain destabilization, as mutations aimed at refolding the leukemic variant also result in rescuing the G-quadruplex–binding activity and nucleolar localization. Finally, we show that treatment of cells with a G-quadruplex selective ligand results in wild-type NPM1 dislocation from nucleoli into nucleoplasm. In conclusion, this work establishes a direct correlation between NPM1 G-quadruplex binding at rDNA and its nucleolar localization, which is impaired in the acute myeloid leukemia-associated protein variants. 相似文献
125.
126.
127.
The restriction of invasion biology to non‐native species has been laid down as one founding principle of the discipline by many researchers. However, this split between native and non‐native species is highly controversial. Using a phenomenological approach and a more pragmatic examination of biological invasions, the present paper discusses how this dichotomy has restricted the relevance of the field, both from theoretical and practical viewpoints. We advocate the emergence of a broader disciplinary field. 相似文献
128.
New records of Cynipid gall wasps and inquilines for the Italian peninsula and Sicily and their new host plants for the Palaearctic Region are listed and commented on. Among them we find: Cerroneuroterus cerrifloralis (Müllner 1901) as new for Italy and new for the Palaearctic region as host on Quercus suber; Andricus multiplicatus Giraud 1859 on Q. suber, as new host for the Palaearctic region; Aylax papaveris (Perris 1839), reported in Italy over a century ago, but later overlooked; Cerroneuroterus minutulus (Giraud 1859), also reported more than a century ago from Sicily, but later overlooked. Among the inquilines are here listed: Synergus variabilis Mayr 1872, emerged from Janetia cerris (Kollar 1850) galls (Diptera Cecidomyiidae), and found for the first time in the Palaearctic Region as host on Q. suber; Saphonecrus haimi (Mayr 1872) and Saphonecrus barbotini Pujade-Villar & Nieves-Aldrey 1986, are new records for Italy. 相似文献
129.
Wei-Chien Hung Shih-Hsun Chen Colin D. Paul Kimberly M. Stroka Ying-Chun Lo Joy T. Yang Konstantinos Konstantopoulos 《The Journal of cell biology》2013,202(5):807-824
Using a microchannel assay, we demonstrate that cells adopt distinct signaling strategies to modulate cell migration in different physical microenvironments. We studied α4β1 integrin–mediated signaling, which regulates cell migration pertinent to embryonic development, leukocyte trafficking, and melanoma invasion. We show that α4β1 integrin promotes cell migration through both unconfined and confined spaces. However, unlike unconfined (2D) migration, which depends on enhanced Rac1 activity achieved by preventing α4/paxillin binding, confined migration requires myosin II–driven contractility, which is increased when Rac1 is inhibited by α4/paxillin binding. This Rac1–myosin II cross talk mechanism also controls migration of fibroblast-like cells lacking α4β1 integrin, in which Rac1 and myosin II modulate unconfined and confined migration, respectively. We further demonstrate the distinct roles of myosin II isoforms, MIIA and MIIB, which are primarily required for confined and unconfined migration, respectively. This work provides a paradigm for the plasticity of cells migrating through different physical microenvironments. 相似文献
130.
Ching-Hung Lee Yen-Wei Chen Yun-Tzu Huang Yih-Jiuan Pan Chien-Hsien Lee Shih-Ming Lin Lin-Kun Huang Yueh-Yu Lo Yu-Fen Huang Yu-Di Hsu Shih-Chung Yen Jenn-Kang Hwang Rong-Long Pan 《The Journal of membrane biology》2013,246(12):959-966
H+-translocating pyrophosphatase (H+-PPase, EC 3.6.1.1) plays an important role in acidifying vacuoles by transporting protons across membranes at the expense of pyrophosphate (PPi) hydrolysis. Vigna radiata H+-PPase (VrH+-PPase) contains 16 transmembrane helices (TMs). The hydrophobicity of TM3 is relatively lower than that of most other TMs, and the amino acids in this TM are highly conserved in plants. Furthermore, TM5 and -6, which are the core TMs involving in H+-PPase functions, are near TM3. It is thus proposed that TM3 is associated with H+-PPase activity. To address this possibility, site-directed mutagenesis was applied in this investigation to determine the role of TM3 in VrH+-PPase. Upon alanine/serine substitution, T138 and S142, whose side chains face toward the center TMs, were found to be involved in efficient proton transport. G149/S153 and G160/A164 pairs at the crucial termini of the two GxxxG-like motifs are indispensable in maintaining enzymatic activities and conformational stability. Moreover, stability in the vicinity surrounding G149 is pivotal for efficient expression. S153, M161 and A164 are critical for the K+-mediated stimulation of H+-PPase. Taken together, our results demonstrate that TM3 plays essential roles in PPi hydrolysis, proton transport, expression, and K+ stimulation of H+-PPase. 相似文献