全文获取类型
收费全文 | 2309篇 |
免费 | 155篇 |
国内免费 | 6篇 |
专业分类
2470篇 |
出版年
2023年 | 8篇 |
2022年 | 39篇 |
2021年 | 73篇 |
2020年 | 50篇 |
2019年 | 60篇 |
2018年 | 68篇 |
2017年 | 66篇 |
2016年 | 91篇 |
2015年 | 95篇 |
2014年 | 134篇 |
2013年 | 131篇 |
2012年 | 180篇 |
2011年 | 163篇 |
2010年 | 123篇 |
2009年 | 95篇 |
2008年 | 149篇 |
2007年 | 138篇 |
2006年 | 132篇 |
2005年 | 103篇 |
2004年 | 121篇 |
2003年 | 94篇 |
2002年 | 81篇 |
2001年 | 20篇 |
2000年 | 31篇 |
1999年 | 18篇 |
1998年 | 18篇 |
1997年 | 15篇 |
1996年 | 7篇 |
1995年 | 5篇 |
1994年 | 5篇 |
1992年 | 9篇 |
1991年 | 12篇 |
1989年 | 6篇 |
1988年 | 11篇 |
1987年 | 4篇 |
1986年 | 13篇 |
1985年 | 14篇 |
1984年 | 9篇 |
1983年 | 9篇 |
1982年 | 3篇 |
1980年 | 6篇 |
1978年 | 3篇 |
1977年 | 9篇 |
1976年 | 3篇 |
1975年 | 11篇 |
1974年 | 7篇 |
1973年 | 3篇 |
1972年 | 3篇 |
1971年 | 3篇 |
1965年 | 3篇 |
排序方式: 共有2470条查询结果,搜索用时 15 毫秒
121.
A peptide corresponding to the BH3 region of the proapoptotic protein, BID, could be bound in the cleft of the antiapoptotic protein, BCL-w. This binding induced major conformational rearrangements in both the peptide and protein components of the complex and led to the displacement and unfolding of the BCL-w C-terminal alpha-helix. The structure of BCL-w with a bound BID-BH3 peptide was determined using NMR spectroscopy and molecular docking. These studies confirmed that a region of 16 residues of the BID-BH3 peptide is responsible for its strong binding to BCL-w and BCL-x(L). The interactions of BCL-w and the BID-BH3 peptide complex with dodecylphosphocholine micelles were characterized and showed that the conformational change of BCL-w upon lipid binding occurred at the same time as the release and unfolding of the BH3 peptide. 相似文献
122.
Alexey A. Dmitriev Anna V. Kudryavtseva George S. Krasnov Nadezhda V. Koroban Anna S. Speranskaya Anastasia A. Krinitsina Maxim S. Belenikin Anastasiya V. Snezhkina Asiya F. Sadritdinova Natalya V. Kishlyan Tatiana A. Rozhmina Olga Yu. Yurkevich Olga V. Muravenko Nadezhda L. Bolsheva Nataliya V. Melnikova 《BMC plant biology》2016,16(3):237
123.
Separate and combined exposure of roach Rutilus rutilus embryos during the first 38 h after fertilization to magnetic field (500 Hz, 1.4–1.6 µT) and elevated temperature (23°?) causes morphological responses: decrease in mean values of length and weight of the body, increase in the number of vertebrae, and increase in the number of vertebral anomalies and morphological diversity of vertebral phenotypes. Size–weight characteristics and the number of vertebrae in underyearlings are related to the development of anomalies in its backbone. A method for counting of vertebrae in fish with backbone malformations is suggested. 相似文献
124.
Natalia Morozova Anton Sabantsev Ekaterina Bogdanova Yana Fedorova Anna Maikova Alexey Vedyaykin Andjela Rodic Marko Djordjevic Mikhail Khodorkovskii Konstantin Severinov 《Nucleic acids research》2016,44(2):790-800
Type II restriction-modification (R-M) systems encode a restriction endonuclease that cleaves DNA at specific sites, and a methyltransferase that modifies same sites protecting them from restriction endonuclease cleavage. Type II R-M systems benefit bacteria by protecting them from bacteriophages. Many type II R-M systems are plasmid-based and thus capable of horizontal transfer. Upon the entry of such plasmids into a naïve host with unmodified genomic recognition sites, methyltransferase should be synthesized first and given sufficient time to methylate recognition sites in the bacterial genome before the toxic restriction endonuclease activity appears. Here, we directly demonstrate a delay in restriction endonuclease synthesis after transformation of Escherichia coli cells with a plasmid carrying the Esp1396I type II R-M system, using single-cell microscopy. We further demonstrate that before the appearance of the Esp1396I restriction endonuclease the intracellular concentration of Esp1396I methyltransferase undergoes a sharp peak, which should allow rapid methylation of host genome recognition sites. A mathematical model that satisfactorily describes the observed dynamics of both Esp1396I enzymes is presented. The results reported here were obtained using a functional Esp1396I type II R-M system encoding both enzymes fused to fluorescent proteins. Similar approaches should be applicable to the studies of other R-M systems at single-cell level. 相似文献
125.
Valentin Magidson Jie He Jeffrey G. Ault Christopher B. O’Connell Nachen Yang Irina Tikhonenko Bruce F. McEwen Haixin Sui Alexey Khodjakov 《The Journal of cell biology》2016,212(3):307-319
Kinetochores attach chromosomes to the spindle microtubules and signal the spindle assembly checkpoint to delay mitotic exit until all chromosomes are attached. Light microscopy approaches aimed to indirectly determine distances between various proteins within the kinetochore (termed Delta) suggest that kinetochores become stretched by spindle forces and compact elastically when the force is suppressed. Low Delta is believed to arrest mitotic progression in taxol-treated cells. However, the structural basis of Delta remains unknown. By integrating same-kinetochore light microscopy and electron microscopy, we demonstrate that the value of Delta is affected by the variability in the shape and size of outer kinetochore domains. The outer kinetochore compacts when spindle forces are maximal during metaphase. When the forces are weakened by taxol treatment, the outer kinetochore expands radially and some kinetochores completely lose microtubule attachment, a condition known to arrest mitotic progression. These observations offer an alternative interpretation of intrakinetochore tension and question whether Delta plays a direct role in the control of mitotic progression. 相似文献
126.
Zhenrong Xu Salvacion Cacatian Jing Yuan Robert D. Simpson Lanqi Jia Wei Zhao Colin M. Tice Patrick T. Flaherty Joan Guo Alexey Ishchenko Suresh B. Singh Zhongren Wu Brian M. McKeever Boyd B. Scott Yuri Bukhtiyarov Jennifer Berbaum Jennifer Mason Reshma Panemangalore Maria Grazia Cappiello Ross Bentley David A. Claremon 《Bioorganic & medicinal chemistry letters》2010,20(2):694-699
Structure-guided drug design led to new alkylamine renin inhibitors with improved in vitro and in vivo potency. Lead compound 21a, has an IC50 of 0.83 nM for the inhibition of human renin in plasma (PRA). Oral administration of 21a at 10 mg/kg resulted in >20 h reduction of blood pressure in a double transgenic rat model of hypertension. 相似文献
127.
Kathy Zhang Melissa L Geddie Neeraj Kohli Tad Kornaga Dmitri B Kirpotin Yang Jiao Rachel Rennard Daryl C Drummond Ulrik B Nielsen Lihui Xu Alexey A Lugovskoy 《MABS-AUSTIN》2015,7(1):42-52
Antibody-targeted nanoparticles have the potential to significantly increase the therapeutic index of cytotoxic anti-cancer therapies by directing them to tumor cells. Using antibodies or their fragments requires careful engineering because multiple parameters, including affinity, internalization rate and stability, all need to be optimized. Here, we present a case study of the iterative engineering of a single chain variable fragment (scFv) for use as a targeting arm of a liposomal cytotoxic nanoparticle. We describe the effect of the orientation of variable domains, the length and composition of the interdomain protein linker that connects VH and VL, and stabilizing mutations in both the framework and complementarity-determining regions (CDRs) on the molecular properties of the scFv. We show that variable domain orientation can alter cross-reactivity to murine antigen while maintaining affinity to the human antigen. We demonstrate that tyrosine residues in the CDRs make diverse contributions to the binding affinity and biophysical properties, and that replacement of non-essential tyrosines can improve the stability and bioactivity of the scFv. Our studies demonstrate that a comprehensive engineering strategy may be required to identify a scFv with optimal characteristics for nanoparticle targeting. 相似文献
128.
Using a mathematical modeling technique, possible spatial mechanisms of processing information by the ampullae of Lorenzini were investigated in the skate during detection of the dipole electric field corresponding in the first approximation to the bioelectric fields of marine vertebrates and invertebrates. Stationary voltage distribution in the inhomogeneous environment was calculated numerically. An unlimited volume of seawater was used as the environment into which a slim disk was placed simulating the body of the fish, which served to create inhomogeneity. When the dipole axis was on the same plane as the disk, distortion in the voltage distribution was negligible. On occasions when the dipole was perpendicular to the plane of the disk, the electrical field energy absorbed by ampullary groups decreased significantly. Calculations suggested that by reorienting its body the fish is able to phase out signals coming from dipoles with their axes on different planes from that of the skate's body.I. P. Pavlov Institute of Physiology, Academy of Sciences of the USSR, Leningrad. Translated from Neirofiziologiya, Vol. 17, No. 5, pp. 660–665, September–October, 1985. 相似文献
129.
Andrey V. Mardanov Galina B. Slododkina Alexander I. Slobodkin Alexey V. Beletsky Sergey N. Gavrilov Ilya V. Kublanov Elizaveta A. Bonch-Osmolovskaya Konstantin G. Skryabin Nikolai V. Ravin 《Applied and environmental microbiology》2015,81(3):1003-1012
Geoglobus acetivorans is a hyperthermophilic anaerobic euryarchaeon of the order Archaeoglobales isolated from deep-sea hydrothermal vents. A unique physiological feature of the members of the genus Geoglobus is their obligate dependence on Fe(III) reduction, which plays an important role in the geochemistry of hydrothermal systems. The features of this organism and its complete 1,860,815-bp genome sequence are described in this report. Genome analysis revealed pathways enabling oxidation of molecular hydrogen, proteinaceous substrates, fatty acids, aromatic compounds, n-alkanes, and organic acids, including acetate, through anaerobic respiration linked to Fe(III) reduction. Consistent with the inability of G. acetivorans to grow on carbohydrates, the modified Embden-Meyerhof pathway encoded by the genome is incomplete. Autotrophic CO2 fixation is enabled by the Wood-Ljungdahl pathway. Reduction of insoluble poorly crystalline Fe(III) oxide depends on the transfer of electrons from the quinone pool to multiheme c-type cytochromes exposed on the cell surface. Direct contact of the cells and Fe(III) oxide particles could be facilitated by pilus-like appendages. Genome analysis indicated the presence of metabolic pathways for anaerobic degradation of aromatic compounds and n-alkanes, although an ability of G. acetivorans to grow on these substrates was not observed in laboratory experiments. Overall, our results suggest that Geoglobus species could play an important role in microbial communities of deep-sea hydrothermal vents as lithoautotrophic producers. An additional role as decomposers would close the biogeochemical cycle of carbon through complete mineralization of various organic compounds via Fe(III) respiration. 相似文献
130.
Ramil N Nurtdinov Alexey D Neverov Alexander V Favorov Andrey A Mironov Mikhail S Gelfand 《BMC evolutionary biology》2007,7(1):249