全文获取类型
收费全文 | 415篇 |
免费 | 19篇 |
专业分类
434篇 |
出版年
2023年 | 4篇 |
2022年 | 7篇 |
2021年 | 22篇 |
2020年 | 4篇 |
2019年 | 10篇 |
2018年 | 14篇 |
2017年 | 11篇 |
2016年 | 18篇 |
2015年 | 24篇 |
2014年 | 16篇 |
2013年 | 34篇 |
2012年 | 37篇 |
2011年 | 27篇 |
2010年 | 24篇 |
2009年 | 10篇 |
2008年 | 18篇 |
2007年 | 22篇 |
2006年 | 18篇 |
2005年 | 23篇 |
2004年 | 21篇 |
2003年 | 13篇 |
2002年 | 13篇 |
2001年 | 1篇 |
2000年 | 3篇 |
1999年 | 1篇 |
1998年 | 5篇 |
1997年 | 3篇 |
1996年 | 1篇 |
1995年 | 2篇 |
1989年 | 2篇 |
1988年 | 4篇 |
1987年 | 2篇 |
1985年 | 1篇 |
1984年 | 2篇 |
1983年 | 1篇 |
1981年 | 1篇 |
1979年 | 1篇 |
1976年 | 1篇 |
1973年 | 2篇 |
1972年 | 2篇 |
1971年 | 2篇 |
1970年 | 2篇 |
1966年 | 2篇 |
1942年 | 1篇 |
1939年 | 2篇 |
排序方式: 共有434条查询结果,搜索用时 0 毫秒
121.
Terziyska N Lutz T Kozany C Mokranjac D Mesecke N Neupert W Herrmann JM Hell K 《FEBS letters》2005,579(1):179-184
Many proteins located in the intermembrane space (IMS) of mitochondria are characterized by a low molecular mass, contain highly conserved cysteine residues and coordinate metal ions. Studies on one of these proteins, Tim13, revealed that net translocation across the outer membrane is driven by metal-dependent folding in the IMS . We have identified an essential component, Mia40/Tim40/Ykl195w, with a highly conserved domain in the IMS that is able to bind zinc and copper ions. In cells lacking Mia40, the endogenous levels of Tim13 and other metal-binding IMS proteins are strongly reduced due to the impaired import of these proteins. Furthermore, Mia40 directly interacts with newly imported Tim13 protein. We conclude that Mia40 is the first essential component of a specific translocation pathway of metal-binding IMS proteins. 相似文献
122.
The catenin, p120ctn, is a common membrane-associated protein in various epithelial and non-epithelial cells and tissues 总被引:4,自引:0,他引:4
The cadherin-binding catenin p120ctn was originally identified as an Src-tyrosine kinase substrate. More recently, p120ctn has been shown in some cell types to be associated with catenin/cadherin complexes of adherens junctions. To address the question whether p120ctn is restricted to certain cell types or whether it is a general cellular component we investigated tissue distribution of p120ctn by immunohistochemistry and immunoblotting in the rat. We found p120ctn to be widely distributed in several tissues where it is mainly restricted to the plasma membrane. In various epithelia p120ctn was found in association with different adherens junctions such as the zonula adherens and puncta adherentia. In addition, p120ctn was localized along infoldings of the basal cell membrane, most prominently in renal proximal and distal tubules. pl20ctn was not restricted to epithelia. It was also found at intercalated discs of cardiomyocytes. In the nervous system, immunostaining was particularly prominent in areas rich in synapses suggesting that pl20ctn is a component of synaptic adherens junctions as well. By immunoblotting, four different isoforms of pl20ctn could be detected displaying similar electrophoretic mobilities as the isoforms 1A, 1B, 2A, and 2B reported from mice. Whereas all epithelia assayed contained at least two isoforms, testis, heart, brain, and retina contained a single 110-kDa band that corresponds to isoform 1B in mice. 相似文献
123.
Jeck N Schlingmann KP Reinalter SC Kömhoff M Peters M Waldegger S Seyberth HW 《American journal of physiology. Regulatory, integrative and comparative physiology》2005,288(4):R782-R795
The molecular basis of inherited salt-losing tubular disorders with secondary hypokalemia has become much clearer in the past two decades. Two distinct segments along the nephron turned out to be affected, the thick ascending limb of Henle's loop and the distal convoluted tubule, accounting for two major clinical phenotypes, hyperprostaglandin E syndrome and Bartter-Gitelman syndrome. To date, inactivating mutations have been detected in six different genes encoding for proteins involved in renal transepithelial salt transport. Careful examination of genetically defined patients ("human knockouts") allowed us to determine the individual role of a specific protein and its contribution to the overall process of renal salt reabsorption. The recent generation of several genetically engineered mouse models that are deficient in orthologous genes further enabled us to compare the human phenotype with the animal models, revealing some unexpected interspecies differences. As the first line treatment in hyperprostaglandin E syndrome includes cyclooxygenase inhibitors, we propose some hypotheses about the mysterious role of PGE(2) in the etiology of renal salt-losing disorders. 相似文献
124.
Recent work has indicated that fruit flies (Drosophila melanogaster) can be used in nociception research. Genetic screening identified a gene, painless, that is required for thermal and mechanical nociception in Drosophila larvae. On the other hand, pharmacological techniques and noxious heat were used to assay antinocieceptive behavior in intact adult Drosophila. In general, animal models for pain research are bound by ethical concerns. Since no serious ethical controversies have been raised regarding experiments in insects, Drosophila may be, for the time being an ethically acceptable animal model for combined genetic and pharmacological analgesia research. 相似文献
125.
126.
Bistable Forespore Engulfment in Bacillus subtilis by a Zipper Mechanism in Absence of the Cell Wall
Nikola Ojkic Javier López-Garrido Kit Pogliano Robert G. Endres 《PLoS computational biology》2014,10(10)
To survive starvation, the bacterium Bacillus subtilis forms durable spores. The initial step of sporulation is asymmetric cell division, leading to a large mother-cell and a small forespore compartment. After division is completed and the dividing septum is thinned, the mother cell engulfs the forespore in a slow process based on cell-wall degradation and synthesis. However, recently a new cell-wall independent mechanism was shown to significantly contribute, which can even lead to fast engulfment in 60 of the cases when the cell wall is completely removed. In this backup mechanism, strong ligand-receptor binding between mother-cell protein SpoIIIAH and forespore-protein SpoIIQ leads to zipper-like engulfment, but quantitative understanding is missing. In our work, we combined fluorescence image analysis and stochastic Langevin simulations of the fluctuating membrane to investigate the origin of fast bistable engulfment in absence of the cell wall. Our cell morphologies compare favorably with experimental time-lapse microscopy, with engulfment sensitive to the number of SpoIIQ-SpoIIIAH bonds in a threshold-like manner. By systematic exploration of model parameters, we predict regions of osmotic pressure and membrane-surface tension that produce successful engulfment. Indeed, decreasing the medium osmolarity in experiments prevents engulfment in line with our predictions. Forespore engulfment may thus not only be an ideal model system to study decision-making in single cells, but its biophysical principles are likely applicable to engulfment in other cell types, e.g. during phagocytosis in eukaryotes. 相似文献
127.
Martin Sikora Meredith L. Carpenter Andres Moreno-Estrada Brenna M. Henn Peter A. Underhill Federico Sánchez-Quinto Ilenia Zara Maristella Pitzalis Carlo Sidore Fabio Busonero Andrea Maschio Andrea Angius Chris Jones Javier Mendoza-Revilla Georgi Nekhrizov Diana Dimitrova Nikola Theodossiev Timothy T. Harkins Andreas Keller Frank Maixner Albert Zink Goncalo Abecasis Serena Sanna Francesco Cucca Carlos D. Bustamante 《PLoS genetics》2014,10(5)
Genome sequencing of the 5,300-year-old mummy of the Tyrolean Iceman, found in 1991 on a glacier near the border of Italy and Austria, has yielded new insights into his origin and relationship to modern European populations. A key finding of that study was an apparent recent common ancestry with individuals from Sardinia, based largely on the Y chromosome haplogroup and common autosomal SNP variation. Here, we compiled and analyzed genomic datasets from both modern and ancient Europeans, including genome sequence data from over 400 Sardinians and two ancient Thracians from Bulgaria, to investigate this result in greater detail and determine its implications for the genetic structure of Neolithic Europe. Using whole-genome sequencing data, we confirm that the Iceman is, indeed, most closely related to Sardinians. Furthermore, we show that this relationship extends to other individuals from cultural contexts associated with the spread of agriculture during the Neolithic transition, in contrast to individuals from a hunter-gatherer context. We hypothesize that this genetic affinity of ancient samples from different parts of Europe with Sardinians represents a common genetic component that was geographically widespread across Europe during the Neolithic, likely related to migrations and population expansions associated with the spread of agriculture. 相似文献
128.
Mutations in Global Regulators Lead to Metabolic Selection during Adaptation to Complex Environments
Gerda Saxer Michael D. Krepps Eric D. Merkley Charles Ansong Brooke L. Deatherage Kaiser Marie-Thérèse Valovska Nikola Ristic Ping T. Yeh Vittal P. Prakash Owen P. Leiser Luay Nakhleh Henry S. Gibbons Helen W. Kreuzer Yousif Shamoo 《PLoS genetics》2014,10(12)
Adaptation to ecologically complex environments can provide insights into the evolutionary dynamics and functional constraints encountered by organisms during natural selection. Adaptation to a new environment with abundant and varied resources can be difficult to achieve by small incremental changes if many mutations are required to achieve even modest gains in fitness. Since changing complex environments are quite common in nature, we investigated how such an epistatic bottleneck can be avoided to allow rapid adaptation. We show that adaptive mutations arise repeatedly in independently evolved populations in the context of greatly increased genetic and phenotypic diversity. We go on to show that weak selection requiring substantial metabolic reprogramming can be readily achieved by mutations in the global response regulator arcA and the stress response regulator rpoS. We identified 46 unique single-nucleotide variants of arcA and 18 mutations in rpoS, nine of which resulted in stop codons or large deletions, suggesting that subtle modulations of ArcA function and knockouts of rpoS are largely responsible for the metabolic shifts leading to adaptation. These mutations allow a higher order metabolic selection that eliminates epistatic bottlenecks, which could occur when many changes would be required. Proteomic and carbohydrate analysis of adapting E. coli populations revealed an up-regulation of enzymes associated with the TCA cycle and amino acid metabolism, and an increase in the secretion of putrescine. The overall effect of adaptation across populations is to redirect and efficiently utilize uptake and catabolism of abundant amino acids. Concomitantly, there is a pronounced spread of more ecologically limited strains that results from specialization through metabolic erosion. Remarkably, the global regulators arcA and rpoS can provide a “one-step” mechanism of adaptation to a novel environment, which highlights the importance of global resource management as a powerful strategy to adaptation. 相似文献
129.
Cocca Walter Žagar Anamarija Sillero Neftalí Jowers Michael J. Krofel Miha Lužnik Martina Podnar Martina Tvrtković Nikola Carretero Miguel A. Crottini Angelica 《Conservation Genetics》2021,22(3):483-498
Conservation Genetics - The Horvath’s rock lizard Iberolacerta horvathi (Méhely, 1904) is an understudied lacertid species, which is geographically isolated from its congeners and... 相似文献
130.
Kolundžić N Bojić-Trbojević Ž Kovačević T Stefanoska I Kadoya T Vićovac L 《PloS one》2011,6(12):e28514