全文获取类型
收费全文 | 4917篇 |
免费 | 60篇 |
国内免费 | 5篇 |
专业分类
4982篇 |
出版年
2024年 | 56篇 |
2023年 | 358篇 |
2022年 | 239篇 |
2021年 | 288篇 |
2020年 | 364篇 |
2019年 | 450篇 |
2018年 | 428篇 |
2017年 | 302篇 |
2016年 | 371篇 |
2015年 | 206篇 |
2014年 | 461篇 |
2013年 | 923篇 |
2012年 | 47篇 |
2011年 | 56篇 |
2010年 | 36篇 |
2009年 | 17篇 |
2008年 | 22篇 |
2007年 | 23篇 |
2006年 | 7篇 |
2005年 | 50篇 |
2004年 | 34篇 |
2003年 | 25篇 |
2002年 | 23篇 |
2001年 | 9篇 |
2000年 | 11篇 |
1999年 | 8篇 |
1998年 | 14篇 |
1997年 | 9篇 |
1996年 | 2篇 |
1995年 | 3篇 |
1994年 | 4篇 |
1993年 | 3篇 |
1992年 | 1篇 |
1991年 | 1篇 |
1989年 | 2篇 |
1986年 | 1篇 |
1985年 | 13篇 |
1984年 | 21篇 |
1983年 | 22篇 |
1982年 | 11篇 |
1981年 | 9篇 |
1980年 | 10篇 |
1979年 | 10篇 |
1978年 | 7篇 |
1977年 | 9篇 |
1976年 | 4篇 |
1975年 | 4篇 |
1974年 | 6篇 |
1973年 | 2篇 |
排序方式: 共有4982条查询结果,搜索用时 0 毫秒
991.
Xin Chen Srishti Devarajan Natasha Danda Chris Williams 《Journal of molecular biology》2018,430(11):1545-1558
The import of matrix proteins into peroxisomes in yeast requires the action of the ubiquitin-conjugating enzyme Pex4p and a complex consisting of the ubiquitin E3 ligases Pex2p, Pex10p and Pex12p. Together, this peroxisomal ubiquitination machinery is thought to ubiquitinate the cycling receptor protein Pex5p and members of the Pex20p family of co-receptors, a modification that is required for receptor recycling. However, recent reports have demonstrated that this machinery plays a role in additional peroxisome-associated processes. Hence, our understanding of the function of these proteins in peroxisome biology is still incomplete. Here, we identify a role for the peroxisomal ubiquitination machinery in the degradation of the peroxisomal membrane protein Pex13p. Our data demonstrate that Pex13p levels build up in cells lacking members of this machinery and also establish that Pex13p undergoes rapid degradation in wild-type cells. Furthermore, we show that Pex13p is ubiquitinated in wild-type cells and also establish that Pex13p ubiquitination is reduced in cells lacking a functional peroxisomal E3 ligase complex. Finally, deletion of PEX2 causes Pex13p to build up at the peroxisomal membrane. Taken together, our data provide further evidence that the role of the peroxisomal ubiquitination machinery in peroxisome biology goes much deeper than receptor recycling alone. 相似文献
992.
Kiyoto Kamagata Eriko Mano Kana Ouchi Saori Kanbayashi Reid C. Johnson 《Journal of molecular biology》2018,430(5):655-667
Architectural DNA-binding proteins function to regulate diverse DNA reactions and have the defining property of significantly changing DNA conformation. Although the 1D movement along DNA by other types of DNA-binding proteins has been visualized, the mobility of architectural DNA-binding proteins on DNA remains unknown. Here, we applied single-molecule fluorescence imaging on arrays of extended DNA molecules to probe the binding dynamics of three structurally distinct architectural DNA-binding proteins: Nhp6A, HU, and Fis. Each of these proteins was observed to move along DNA, and the salt concentration independence of the 1D diffusion implies sliding with continuous contact to DNA. Nhp6A and HU exhibit a single sliding mode, whereas Fis exhibits two sliding modes. Based on comparison of the diffusion coefficients and sizes of many DNA binding proteins, the architectural proteins are categorized into a new group distinguished by an unusually high free-energy barrier for 1D diffusion. The higher free-energy barrier for 1D diffusion by architectural proteins can be attributed to the large DNA conformational changes that accompany binding and impede rotation-coupled movement along the DNA grooves. 相似文献
993.
Takamitsu Haruyama Takayuki Uchihashi Yutaro Yamada Noriyuki Kodera Toshio Ando Hiroki Konno 《Journal of molecular biology》2018,430(5):602-610
The function of ubiquitous 2-Cys peroxiredoxins (Prxs) can be converted alternatively from peroxidases to molecular chaperones. This conversion has been reported to occur by the formation of high-molecular-weight (HMW) complexes upon overoxidation of or ATP/ADP binding to 2-Cys Prxs, but its mechanism is not well understood. Here, we show that upon binding to phosphatidylserine or phosphatidylglycerol dimeric human 2-Cys PrxII (hPrxII) is assembled to trefoil-shaped small oligomers (possibly hexamers) with full chaperone and null peroxidase activities. Spherical HMW complexes are formed, only when phosphatidylserine or phosphatidylglycerol is bound to overoxidized or ATP/ADP-bound hPrxII. The spherical HMW complexes are lipid vesicles covered with trefoil-shaped oligomers arranged in a hexagonal lattice pattern. Thus, these lipids with a net negative charge, which can be supplied by increased membrane trafficking under oxidative stress, are essential for the structural and functional switch of hPrxII and possibly most 2-Cys Prxs. 相似文献
994.
995.
Sneha Munshi Divya Rajendran Athi N. Naganathan 《Journal of molecular biology》2018,430(17):2688-2694
Many intrinsically disordered proteins switch between unfolded and folded-like forms in the presence of their binding partner. The possibility of a pre-equilibrium between the two macrostates is challenging to discern given the complex conformational landscape. Here, we show that CytR, a disordered DNA-binding domain, samples a folded-like excited state in its native ensemble through equilibrium multi-probe spectroscopy, kinetics and an Ising-like statistical mechanical model. The population of the excited state increases upon stabilization of the native ensemble with an osmolyte, while decreasing with increasing temperatures. A conserved proline residue, the mutation of which weakens the binding affinity to the target promoter, is found to uniquely control the population of the minor excited state. Semi-quantitative statistical mechanical modeling reveals that the conformational diffusion coefficient of disordered CytR is an order of magnitude slower than the estimates from folded domains. The osmolyte and proline mutation smoothen and roughen up the landscape, respectively, apart from modulation of populations. Our work uncovers general strategies to probe for excited structured states in disordered ensembles, and to measure and modulate the roughness of the disordered landscapes, inter-conversion rates of species and their populations. 相似文献
996.
《Cryobiology》2018
ObjectivesTo describe immunological consequences induced by cryoablation against H22 cells in vivo.MethodsAdult BALB/c mice underwent subcutaneous implantation of H22 cells. All of them were assigned into three groups randomly: group A (false surgery), group B (cryoablation) and group C (cryoablation plus Freund's adjuvant). Animals were sacrificed 1, 2 and 3 weeks after treatment. Serum IFN-γ and IL-4, Th1/Th2 in spleens and cytotoxicity were detected.ResultsCompared with that of group A, (1) INF-γ of group B was higher, but IL-4 was lower; cryoablation plus Freund's adjuvant enhanced these effects. (2) Th1/Th2 rose significantly in both group B and group C. (3) Strong cytolytic activity against H22 cells of group B and group C was found on day 7, 14 and 21.ConclusionsOur study showed a marked shift toward Th1 and IFN-γ expression after cryoablation, with an immuno-stimulatory effect against murine H22 hepatoma Cell. 相似文献
997.
998.
Cisplatin (cis-diamminedichloroplatinum) is a common chemotherapeutic drug that reacts with the N7 atoms of adjacent guanines in DNA to form the Pt-1,2-d(GpG) intrastrand cross-link (Pt-GG), a major product to block DNA replication. Translesion DNA synthesis has been implicated in chemoresistance during cisplatin treatment of cancer due to Pt-GG lesion bypass. Gene knockdown studies in human cells have indicated a role for polκ during translesion synthesis of the Pt-GG lesion. However, the bypass activity of polκ with cisplatin lesions has not been well characterized. In this study, we investigated polκ's ability to bypass Pt-GG lesion in vitro and determined two crystal structures of polκ in complex with Pt-GG DNA. The ternary complex structures represent two consecutive stages of lesion bypass: nucleotide insertion opposite the 5′G (Pt-GG2) and primer extension immediately after the lesion (Pt-GG3). Our biochemical data showed that polκ is very efficient and accurate in extending DNA primers after the first G of the Pt-GG lesion. The structures demonstrate that the efficiency and accuracy is achieved by stably accommodating the bases with the cisplatin adduct in the active site for proper Watson–Crick base pairing with the incoming nucleotide in both the second insertion and post-insertion complexes. Our studies suggest that polκ works as an extender for efficient replication of the Pt-GG lesion in cells. This work holds promise for considering polκ, along with polη, as potential targets for drug design, which together could improve the efficacy of cisplatin treatment for cancer therapy. 相似文献
999.
Florian Malard Nadine Assrir Mouad Alami Samir Messaoudi Ewen Lescop Tâp Ha-Duong 《Journal of molecular biology》2018,430(11):1621-1639
The translationally controlled tumor protein (TCTP) is a multifunctional protein that may interact with many other biomolecules, including itself. The experimental determinations of TCTP structure revealed a folded core domain and an intrinsically disordered region, which includes the first highly conserved TCTP signature, but whose role in the protein functions remains to be elucidated. In this work, we combined NMR experiments and MD simulations to characterize the conformational ensemble of the TCTP intrinsically disordered loop, in the presence or not of calcium ions and with or without the phosphorylation of Ser46 and Ser64. Our results show that these changes in the TCTP electrostatic conditions induce significant shifts of its conformational ensemble toward structures more or less extended in which the disordered loop is pulled away or folded against the core domain. Particularly, these conditions impact the transient contacts between the two highly conserved signatures of the protein. Moreover, both experimental and theoretical data show that the interface of the non-covalent TCTP dimerization involves its second signature which suggests that this region might be involved in protein–protein interaction. We also show that calcium hampers the formation of TCTP dimers, likely by favoring the competitive binding of the disordered loop to the dimerization interface. All together, we propose that the TCTP intrinsically disordered region is involved in remodeling the core domain surface to modulate its accessibility to its partners in response to a variety of cellular conditions. 相似文献
1000.
Jonathon A. Ditlev Lindsay B. Case Michael K. Rosen 《Journal of molecular biology》2018,430(23):4666-4684
Biomolecular condensates are two- and three-dimensional compartments in eukaryotic cells that concentrate specific collections of molecules without an encapsulating membrane. Many condensates behave as dynamic liquids and appear to form through liquid–liquid phase separation driven by weak, multivalent interactions between macromolecules. In this review, we discuss current models and data regarding the control of condensate composition, and we describe our current understanding of the composition of representative condensates including PML nuclear bodies, P-bodies, stress granules, the nucleolus, and two-dimensional membrane localized LAT and nephrin clusters. Specific interactions, such as interactions between modular binding domains, weaker interactions between intrinsically disorder regions and nucleic acid base pairing, and nonspecific interactions, such as electrostatic interactions and hydrophobic interactions, influence condensate composition. Understanding how specific condensate composition is determined is essential to understanding condensates as biochemical entities and ultimately discerning their cellular and organismic functions. 相似文献