全文获取类型
收费全文 | 7297篇 |
免费 | 751篇 |
国内免费 | 3篇 |
出版年
2023年 | 48篇 |
2022年 | 130篇 |
2021年 | 222篇 |
2020年 | 130篇 |
2019年 | 144篇 |
2018年 | 181篇 |
2017年 | 138篇 |
2016年 | 237篇 |
2015年 | 429篇 |
2014年 | 453篇 |
2013年 | 536篇 |
2012年 | 699篇 |
2011年 | 604篇 |
2010年 | 359篇 |
2009年 | 325篇 |
2008年 | 465篇 |
2007年 | 428篇 |
2006年 | 410篇 |
2005年 | 340篇 |
2004年 | 320篇 |
2003年 | 277篇 |
2002年 | 235篇 |
2001年 | 93篇 |
2000年 | 65篇 |
1999年 | 52篇 |
1998年 | 68篇 |
1997年 | 42篇 |
1996年 | 33篇 |
1995年 | 30篇 |
1994年 | 30篇 |
1993年 | 33篇 |
1992年 | 37篇 |
1991年 | 31篇 |
1990年 | 29篇 |
1989年 | 23篇 |
1988年 | 34篇 |
1987年 | 21篇 |
1986年 | 18篇 |
1985年 | 28篇 |
1984年 | 26篇 |
1983年 | 16篇 |
1982年 | 22篇 |
1981年 | 14篇 |
1980年 | 19篇 |
1979年 | 11篇 |
1978年 | 13篇 |
1976年 | 14篇 |
1973年 | 10篇 |
1972年 | 11篇 |
1969年 | 10篇 |
排序方式: 共有8051条查询结果,搜索用时 31 毫秒
961.
Estrada-Cuzcano A Neveling K Kohl S Banin E Rotenstreich Y Sharon D Falik-Zaccai TC Hipp S Roepman R Wissinger B Letteboer SJ Mans DA Blokland EA Kwint MP Gijsen SJ van Huet RA Collin RW Scheffer H Veltman JA Zrenner E;European Retinal Disease Consortium den Hollander AI Klevering BJ Cremers FP 《American journal of human genetics》2012,90(1):102-109
Cone-rod dystrophy (CRD) and retinitis pigmentosa (RP) are clinically and genetically overlapping heterogeneous retinal dystrophies. By using homozygosity mapping in an individual with autosomal-recessive (ar) RP from a consanguineous family, we identified three sizeable homozygous regions, together encompassing 46 Mb. Next-generation sequencing of all exons, flanking intron sequences, microRNAs, and other highly conserved genomic elements in these three regions revealed a homozygous nonsense mutation (c.497T>A [p.Leu166∗]) in C8orf37, located on chromosome 8q22.1. This mutation was not present in 150 ethnically matched control individuals, single-nucleotide polymorphism databases, or the 1000 Genomes database. Immunohistochemical studies revealed C8orf37 localization at the base of the primary cilium of human retinal pigment epithelium cells and at the base of connecting cilia of mouse photoreceptors. C8orf37 sequence analysis of individuals who had retinal dystrophy and carried conspicuously large homozygous regions encompassing C8orf37 revealed a homozygous splice-site mutation (c.156−2A>G) in two siblings of a consanguineous family and homozygous missense mutations (c.529C>T [p.Arg177Trp]; c.545A>G [p.Gln182Arg]) in siblings of two other consanguineous families. The missense mutations affect highly conserved amino acids, and in silico analyses predicted that both variants are probably pathogenic. Clinical assessment revealed CRD in four individuals and RP with early macular involvement in two individuals. The two CRD siblings with the c.156−2A>G mutation also showed unilateral postaxial polydactyly. These results underline the importance of disrupted ciliary processes in the pathogenesis of retinal dystrophies. 相似文献
962.
Y Dong L Zhang S Zhang Y Bai H Chen X Sun W Yong W Li SC Colvin SJ Rhodes W Shou ZY Zhang 《The Journal of biological chemistry》2012,287(38):32172-32179
The PRL (phosphatase of regenerating liver) phosphatases are implicated in the control of cell proliferation and invasion. Aberrant PRL expression is associated with progression and metastasis of multiple cancers. However, the specific in vivo function of the PRLs remains elusive. Here we show that deletion of PRL2, the most ubiquitously expressed PRL family member, leads to impaired placental development and retarded growth at both embryonic and adult stages. Ablation of PRL2 inactivates Akt and blocks glycogen cell proliferation, resulting in reduced spongiotrophoblast and decidual layers in the placenta. These structural defects cause placental hypotrophy and insufficiency, leading to fetal growth retardation. We demonstrate that the tumor suppressor PTEN is elevated in PRL2-deficient placenta. Biochemical analyses indicate that PRL2 promotes Akt activation by down-regulating PTEN through the proteasome pathway. This study provides the first evidence that PRL2 is required for extra-embryonic development and associates the oncogenic properties of PRL2 with its ability to negatively regulate PTEN, thereby activating the PI3K-Akt pathway. 相似文献
963.
Shi SY Martin RG Duncan RE Choi D Lu SY Schroer SA Cai EP Luk CT Hopperton KE Domenichiello AF Tang C Naples M Dekker MJ Giacca A Adeli K Wagner KU Bazinet RP Woo M 《The Journal of biological chemistry》2012,287(13):10277-10288
Non-alcoholic fatty liver disease (NAFLD) is becoming the leading cause of chronic liver disease and is now considered to be the hepatic manifestation of the metabolic syndrome. However, the role of steatosis per se and the precise factors required in the progression to steatohepatitis or insulin resistance remain elusive. The JAK-STAT pathway is critical in mediating signaling of a wide variety of cytokines and growth factors. Mice with hepatocyte-specific deletion of Janus kinase 2 (L-JAK2 KO mice) develop spontaneous steatosis as early as 2 weeks of age. In this study, we investigated the metabolic consequences of jak2 deletion in response to diet-induced metabolic stress. To our surprise, despite the profound hepatosteatosis, deletion of hepatic jak2 did not sensitize the liver to accelerated inflammatory injury on a prolonged high fat diet (HFD). This was accompanied by complete protection against HFD-induced whole-body insulin resistance and glucose intolerance. Improved glucose-stimulated insulin secretion and an increase in β-cell mass were also present in these mice. Moreover, L-JAK2 KO mice had progressively reduced adiposity in association with blunted hepatic growth hormone signaling. These mice also exhibited increased resting energy expenditure on both chow and high fat diet. In conclusion, our findings indicate a key role of hepatic JAK2 in metabolism such that its absence completely arrests steatohepatitis development and confers protection against diet-induced systemic insulin resistance and glucose intolerance. 相似文献
964.
Prey can use various camouflage types as defense against predators. One of the most common and important types is background
matching, which occurs if an animal matches the background in color, brightness, and pattern. Although background matching
has been studied intensively, the effects of the resting orientation of prey on the effectiveness of camouflage through background
matching are not well known in natural conditions. Several past experimental studies have been conducted on resting orientation
in the lab often using the visual system of humans. Their results revealed that the detection rates of predators hinge on
the combination of the resting orientation of artificial moths and their background. Here, we studied whether survival rates
of artificial moth-like models depend on their resting orientation in the wild where the visual conditions and detection distances
vary. We used a 2 × 2 design of two resting positions of a horizontally and a vertically striped morph on tree bark. Our results
show that the survival probability of moths depended mainly on the orientation of stripes relative to the vertical structure
of tree bark. Thus, resting orientation relative to background affected survival. After reanalyzing Endler’s (Biol J Linn
Soc 22:187–231, 1984) data on resting habitats of 317 species of North American moths, we found that horizontally striped moths occurred frequently
on small herbs and tree bark. We suggest that it would be beneficial for striped moths to orient non-randomly on strongly
structured background, like furrows of tree bark. We further suggest that background matching was more important than coincident
disruptive coloration in determining the survival rates of our artificial moths. 相似文献
965.
Li YN Radner S French MM Pinzón-Duarte G Daly GH Burgeson RE Koch M Brunken WJ 《Matrix biology》2012,31(2):120-134
Laminins are heterotrimeric extracellular glycoproteins found in, but not confined to, basement membranes (BMs). They are important components in formation of the molecular networks of BMs as well as in cell polarity, cell differentiation and tissue morphogenesis. Each laminin is composed by an α, a β and a γ chain. Previous studies have shown that the γ3 chain is partnered with either the β1 chain (in placenta) or β2 chain (in the CNS) (Libby et al., 2000). Several studies, including our own, suggested that the γ3 chain is expressed in both apical and basal compartments (Koch et al., 1999; Gersdorff et al., 2005; Yan and Cheng, 2006). This study investigates the expression pattern of the γ3 chain in mouse. We developed three new γ3-reactive antibodies, and we show that the γ3 chain is present in BMs. The distribution pattern is considerably more restricted than that of the γ1 chain and within any tissue there is differential deposition into BM compartments. This is particularly true in the retina and brain, where γ3 is uniquely expressed in a subset of the vascular basement membranes and the pial surface. We used conventional genetic ablation techniques to remove the γ3 chain in mice; unlike other laminin null mice (α5, β2, γ1 nulls), these mice live a normal lifespan and have only minor abnormalities, the most striking of which are ectopic granule cells in the cerebellum and an apparent increase in capillary branching in the outer retina. These data support the suggestion that the γ3 chain is deposited in BMs and contributes some unique properties to their function, particularly in the nervous system. 相似文献
966.
Carberry K Wiesenfahrt T Geisler F Stöcker S Gerhardus H Überbach D Davis W Jorgensen E Leube RE Bossinger O 《Development (Cambridge, England)》2012,139(10):1851-1862
The nematode Caenorhabditis elegans is an excellent model system in which to study in vivo organization and function of the intermediate filament (IF) system for epithelial development and function. Using a transgenic ifb-2::cfp reporter strain, a mutagenesis screen was performed to identify mutants with aberrant expression patterns of the IF protein IFB-2, which is expressed in a dense network at the subapical endotube just below the microvillar brush border of intestinal cells. Two of the isolated alleles (kc2 and kc3) were mapped to the same gene, which we refer to as ifo-1 (intestinal filament organizer). The encoded polypeptide colocalizes with IF proteins and F-actin in the intestine. The apical localization of IFO-1 does not rely on IFB-2 but is dependent on LET-413, a basolateral protein involved in apical junction assembly and maintenance of cell polarity. In mutant worms, IFB-2 and IFC-2 are mislocalized in cytoplasmic granules and accumulate in large aggregates at the C. elegans apical junction (CeAJ) in a DLG-1-dependent fashion. Electron microscopy reveals loss of the prominent endotube and disordered but still intact microvilli. Semiquantitative fluorescence microscopy revealed a significant decrease of F-actin, suggesting a general role of IFO-1 in cytoskeletal organization. Furthermore, downregulation of the cytoskeletal organizer ERM-1 and the adherens junction component DLG-1, each of which leads to F-actin reduction on its own, induces a novel synthetic phenotype in ifo-1 mutants resulting in disruption of the lumen. We conclude that IFO-1 is a multipurpose linker between different cytoskeletal components of the C. elegans intestinal terminal web and contributes to proper epithelial tube formation. 相似文献
967.
Interaction of the non-phosphorylated peptide G7-18NATE with Grb7-SH2 domain requires phosphate for enhanced affinity and specificity 总被引:1,自引:0,他引:1
Gunzburg MJ Ambaye ND Del Borgo MP Pero SC Krag DN Wilce MC Wilce JA 《Journal of molecular recognition : JMR》2012,25(1):57-67
Src‐homology (SH2) domains are an attractive target for the inhibition of specific signalling pathways but pose the challenge of developing a truly specific inhibitor. The G7‐18NATE cyclic peptide is reported to specifically inhibit the growth factor receptor bound protein 7 (Grb7) adapter protein, implicated in the progression of several cancer types, via interactions with its SH2 domain. G7‐18NATE effectively inhibits the interaction of Grb7 with ErbB3 and focal adhesion kinase in cell lysates and, with the addition of a cell permeability sequence, inhibits the growth and migration of a number of breast cancer cell lines. It is thus a promising lead in the development of therapeutics targeted to Grb7. Here we investigate the degree to which G7‐18NATE is specific for the Grb7‐SH2 domain compared with closely related SH2 domains including those of Grb10, Grb14, and Grb2 using surface plasmon resonance. We demonstrate that G7‐18NATE binds with micromolar binding affinity to Grb7‐SH2 domain (KD = 4–6 μm ) compared with 50–200 times lower affinity for Grb10, Grb14, and Grb2 but that this specificity depends critically on the presence of phosphate in millimolar concentrations. Other differences in buffer composition, including use of Tris or 2‐(N‐Morpholino)ethanesulfonic acid or varying the pH, do not impact on the interaction. This suggests that under cellular conditions, G7‐18NATE binds with highest affinity to Grb7. In addition, our findings demonstrate that the basis of specificity of G7‐18NATE binding to the Grb7‐SH2 domain is via other than intrinsic structural features of the protein, representing an unexpected mode of molecular recognition. Copyright © 2011 John Wiley & Sons, Ltd. 相似文献
968.
Genetics' demand for increased throughput is driving automatization of behavior analysis far beyond experimental workhorses like circadian monitors and the operant conditioning box. However, the new automation is not just faster: it is also allowing new kinds of experiments, many of which erase the boundaries of the traditional neuroscience disciplines (psychology, ethology and physiology) while producing insight into problems that were otherwise opaque. Ironically, a central theme of current automatization is to improve observation of animals in increasingly naturalistic environments. This is not just a return to 19th century priorities: the new observational methods provide unprecedented quantitation of actions and ever-closer integration with experimentation. 相似文献
969.
Krech K Ruf S Masduki FF Thiele W Bednarczyk D Albus CA Tiller N Hasse C Schöttler MA Bock R 《Plant physiology》2012,159(2):579-591
Photosystem biogenesis in the thylakoid membrane is a highly complicated process that requires the coordinated assembly of nucleus-encoded and chloroplast-encoded protein subunits as well as the insertion of hundreds of cofactors, such as chromophores (chlorophylls, carotenoids) and iron-sulfur clusters. The molecular details of the assembly process and the identity and functions of the auxiliary factors involved in it are only poorly understood. In this work, we have characterized the chloroplast genome-encoded ycf4 (for hypothetical chloroplast reading frame no. 4) gene, previously shown to encode a protein involved in photosystem I (PSI) biogenesis in the unicellular green alga Chlamydomonas reinhardtii. Using stable transformation of the chloroplast genome, we have generated ycf4 knockout plants in the higher plant tobacco (Nicotiana tabacum). Although these mutants are severely affected in their photosynthetic performance, they are capable of photoautotrophic growth, demonstrating that, different from Chlamydomonas, the ycf4 gene product is not essential for photosynthesis. We further show that ycf4 knockout plants are specifically deficient in PSI accumulation. Unaltered expression of plastid-encoded PSI genes and biochemical analyses suggest a posttranslational action of the Ycf4 protein in the PSI assembly process. With increasing leaf age, the contents of Ycf4 and Y3IP1, another auxiliary factor involved in PSI assembly, decrease strongly, whereas PSI contents remain constant, suggesting that PSI is highly stable and that its biogenesis is restricted to young leaves. 相似文献
970.
Understanding the maintenance of sexual reproduction constitutes a difficult problem for evolutionary biologists because of the immediate costs that sex seems to incur. Typically, general benefits to sex and recombination are investigated that might outweigh these costs. However, several factors can strongly influence the complex balance between costs and benefits of sex; these include constraints on the evolution of asexuality, ecological differentiation, and certain lif-history traits. We review these factors and their empirical support for the first time in a unified framework and find that they can reduce the costs of sex, circumvent them, or make them inapplicable. These factors can even tip the scales to a net benefit for sex. The reviewed factors affect species and species groups differently, and we conclude consequently that understanding the maintenance of sex could turn out to be more species-specific than commonly assumed. Interestingly, our study suggests that, in some species, no general benefits to sex and recombination might be needed to understand the maintenance of sex, as in our case study of dandelions. 相似文献