全文获取类型
收费全文 | 362篇 |
免费 | 27篇 |
出版年
2021年 | 6篇 |
2020年 | 5篇 |
2019年 | 2篇 |
2018年 | 7篇 |
2017年 | 5篇 |
2016年 | 9篇 |
2015年 | 14篇 |
2014年 | 18篇 |
2013年 | 26篇 |
2012年 | 27篇 |
2011年 | 20篇 |
2010年 | 12篇 |
2009年 | 14篇 |
2008年 | 17篇 |
2007年 | 13篇 |
2006年 | 11篇 |
2005年 | 14篇 |
2004年 | 12篇 |
2003年 | 12篇 |
2002年 | 7篇 |
2001年 | 11篇 |
2000年 | 8篇 |
1999年 | 11篇 |
1998年 | 2篇 |
1997年 | 2篇 |
1995年 | 2篇 |
1993年 | 2篇 |
1992年 | 9篇 |
1991年 | 6篇 |
1990年 | 6篇 |
1989年 | 6篇 |
1988年 | 8篇 |
1987年 | 5篇 |
1986年 | 8篇 |
1985年 | 5篇 |
1983年 | 4篇 |
1980年 | 2篇 |
1979年 | 2篇 |
1978年 | 6篇 |
1976年 | 4篇 |
1975年 | 3篇 |
1974年 | 2篇 |
1973年 | 4篇 |
1972年 | 2篇 |
1951年 | 1篇 |
1934年 | 1篇 |
1933年 | 2篇 |
1930年 | 2篇 |
1928年 | 1篇 |
1927年 | 1篇 |
排序方式: 共有389条查询结果,搜索用时 15 毫秒
51.
Arginine-rich cell-penetrating peptides (CPPs) can enter cells non-endocytotically, despite that transport of charge across a membrane should be formally associated with an extremely high Born energy barrier. We studied partitioning of several derivatives of the CPP penetratin in a water-octanol two-phase system in presence of natural phospholipids to explore if solvation by ion-pairing to hydrophobic counter-ions may serve as a mechanism for cell internalisation. We demonstrate that anionic lipids can aid peptide partitioning into octanol. Particularly efficient partitioning into octanol is observed with an arginine-rich penetratin compared to a lysine-rich derivative. Substituting tryptophans for phenylalanines results in poor partitioning into octanol, due to decreased overall peptide hydrophobicity. Partitioning into octanol is dependent of phospholipid type and the peptides induced structural changes in the lipid assemblies found in octanol. Attachment of carboxyfluorescein as a model cargo was found to enhance peptide partitioning into octanol. We discuss our results with respect to theoretical electrostatic energies, empirical hydrophobicity scales and in terms of implications for CPP uptake mechanisms. An important improvement of the theoretical transfer energies is obtained when, instead of singular ions, the insertion of ion-paired dipolar species is considered. 相似文献
52.
The Mitogen-activated protein kinase p38 links Shiga Toxin-dependent signaling and trafficking
下载免费PDF全文
![点击此处可从《Molecular biology of the cell》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Wälchli S Skånland SS Gregers TF Lauvrak SU Torgersen ML Ying M Kuroda S Maturana A Sandvig K 《Molecular biology of the cell》2008,19(1):95-104
Shiga toxin (Stx) binds to the cell, and it is transported via endosomes and the Golgi apparatus to the endoplasmic reticulum and cytosol, where it exerts its toxic effect. We have recently shown that Stx activates the tyrosine kinase Syk, which in turn induces clathrin phosphorylation and up-regulates Stx uptake. Here, we show that toxin-induced signaling can also regulate another step in intracellular Stx transport. We demonstrate that transport of Stx to the Golgi apparatus is dependent on the mitogen-activated protein kinase p38. Treatment of cells with chemical inhibitors or small interfering RNA targeting p38 inhibited Stx transport to the Golgi and reduced Stx toxicity. This p38 dependence is specific to Stx, because transport of the related toxin ricin was not affected by p38 inhibition. Stx rapidly activated p38, and recruited it to early endosomes in a Ca(2+)-dependent manner. Furthermore, agonist-induced oscillations in cytosolic Ca(2+) levels were inhibited upon Stx stimulation, possibly reflecting Stx-dependent local alterations in cytosolic Ca(2+) levels. Intracellular transport of Stx is Ca(2+) dependent, and we provide evidence that Stx activates a signaling cascade involving cross talk between Ca(2+) and p38, to regulate its trafficking to the Golgi apparatus. 相似文献
53.
Andersson R Bruder CE Piotrowski A Menzel U Nord H Sandgren J Hvidsten TR Diaz de Ståhl T Dumanski JP Komorowski J 《Bioinformatics (Oxford, England)》2008,24(6):751-758
MOTIVATION: Copy number profiling methods aim at assigning DNA copy numbers to chromosomal regions using measurements from microarray-based comparative genomic hybridizations. Among the proposed methods to this end, Hidden Markov Model (HMM)-based approaches seem promising since DNA copy number transitions are naturally captured in the model. Current discrete-index HMM-based approaches do not, however, take into account heterogeneous information regarding the genomic overlap between clones. Moreover, the majority of existing methods are restricted to chromosome-wise analysis. RESULTS: We introduce a novel Segmental Maximum A Posteriori approach, SMAP, for DNA copy number profiling. Our method is based on discrete-index Hidden Markov Modeling and incorporates genomic distance and overlap between clones. We exploit a priori information through user-controllable parameterization that enables the identification of copy number deviations of various lengths and amplitudes. The model parameters may be inferred at a genome-wide scale to avoid overfitting of model parameters often resulting from chromosome-wise model inference. We report superior performances of SMAP on synthetic data when compared with two recent methods. When applied on our new experimental data, SMAP readily recognizes already known genetic aberrations including both large-scale regions with aberrant DNA copy number and changes affecting only single features on the array. We highlight the differences between the prediction of SMAP and the compared methods and show that SMAP accurately determines copy number changes and benefits from overlap consideration. 相似文献
54.
Erling S. Nordøy Lars P. Folkow Vladimir Potelov Vitaly Prischemikhin Arnoldus Schytte Blix 《Polar Biology》2008,31(9):1119-1135
Eight adult female harp seals (Pagophilus
groenlandicus) of the White Sea–Barents Sea stock were tagged with satellite-linked dive recorders during the nursing period and followed
from breeding in late February 1995 until moulting in late April 1995. Another ten adult harp seals of both sexes were tagged
and followed from moult in early May 1996 until breeding in late February the following year. Between breeding and moult the
seals were distributed along the coasts of Kola of Russia and eastern Finnmark of Norway, coinciding in time and space with
the spawning capelin (Mallotus villosus). Between moulting and breeding they encircled the entire Barents Sea, mostly in open water, using the water column from
20 to 300 m, and in so doing by and large reflecting the annual migrations of the capelin. Capelin is therefore assumed to
be the main source of prey for the White Sea–Barents Sea stock of harp seals, to be substituted, in part, by amphipods (e.g.
Themisto libellula) in mid-summer and polar cod (Boreogadus saida) and herring (Clupea pallasii) in late autumn and winter. These data provide a baseline for the evaluation of the effects of future climatic change in
the rich Barents Sea ecosystem. 相似文献
55.
Marlys Hammond David G. Washburn Tram H. Hoang Sharada Manns James S. Frazee Hiroko Nakamura Jaclyn R. Patterson Walter Trizna Charlene Wu Leonard M. Azzarano Rakesh Nagilla Melanie Nord Rebecca Trejo Martha S. Head Baoguang Zhao Angela M. Smallwood Kendra Hightower Nicholas J. Laping Christine G. Schnackenberg Scott K. Thompson 《Bioorganic & medicinal chemistry letters》2009,19(15):4441-4445
The lead serum and glucocorticoid-related kinase 1 (SGK1) inhibitors 4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzoic acid (1) and {4-[5-(2-naphthalenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]phenyl}acetic acid (2) suffer from low DNAUC values in rat, due in part to formation and excretion of glucuronic acid conjugates. These PK/glucuronidation issues were addressed either by incorporating a substituent on the 3-phenyl ring ortho to the key carboxylate functionality of 1 or by substituting on the group in between the carboxylate and phenyl ring of 2. Three of these analogs have been identified as having good SGK1 inhibition potency and have DNAUC values suitable for in vivo testing. 相似文献
56.
Questions: Is the red fox a potential vector for epizoochorous seed dispersal? Can seed attachment and retention be predicted from plant and seed traits? Location: Grasslands in southern Norway. Methods: Epizoochorous seed attachment on the red fox was studied by walking a dummy fox through the vegetation and comparing seeds found on the dummy with the estimated seed availability in the vegetation. Seed retention, i.e. the ability of different seeds to stay on the fox, was estimated in a separate experiment. Seed attachment and retention were related to plant and seed traits using statistical models that account for heteroscedasticity and zero‐inflated data. Results: The majority of seeds attached to the fox originated from a few species, but also species without specific seed traits that are supposed to enhance epizoochory attached at least some seeds to the fox. The probability of seed attachment was positively related to plant height, bristle and hooked seed appendages, and negatively related to winged appendages, seed mass, and seed sphericity. Seed retention was positively related to the seed traits bristles, hooks and pappus. For several species, the results indicate a high potential for dispersal over long distances. Conclusions: In modern agricultural landscapes, large herbivores are often restricted in their mobility or are found at low densities, and other animal vectors may therefore be important for seed dispersal. In our study, a range of plant species were able to disperse by attaching seeds to, and having their seeds retained in, the fox fur some distance. We suggest that the red fox may be an important vector for epizoochorous seed dispersal in the agricultural landscape. 相似文献
57.
Kristin Fenton Silje Fismen Annica Hedberg Natalya Seredkina Chris Fenton Elin Synn?ve Mortensen Ole Petter Rekvig 《PloS one》2009,4(12)
Background
Lupus nephritis is characterized by deposition of chromatin fragment-IgG complexes in the mesangial matrix and glomerular basement membranes (GBM). The latter defines end-stage disease.Methodology/Principals
In the present study we determined the impact of antibodies to dsDNA, renal Dnase1 and matrix metalloprotease (MMP) mRNA levels and enzyme activities on early and late events in murine lupus nephritis. The major focus was to analyse if these factors were interrelated, and if changes in their expression explain basic processes accounting for lupus nephritis.Findings
Early phases of nephritis were associated with chromatin-IgG complex deposition in the mesangial matrix. A striking observation was that this event correlated with appearance of anti-dsDNA antibodies and mild or clinically silent nephritis. These events preceded down-regulation of renal Dnase1. Later, renal Dnase1 mRNA level and enzyme activity were reduced, while MMP2 mRNA level and enzyme activity increased. Reduced levels of renal Dnase1 were associated in time with deficient fragmentation of chromatin from dead cells. Large fragments were retained and accumulated in GBM. Also, since chromatin fragments are prone to stimulate Toll-like receptors in e.g. dendritic cells, this may in fact explain increased expression of MMPs.Significance
These scenarios may explain the basis for deposition of chromatin-IgG complexes in glomeruli in early and late stages of nephritis, loss of glomerular integrity and finally renal failure. 相似文献58.
Because the maintenance of proper developmental temperatures during avian incubation is costly to parents, embryos of many species experience pronounced variation in incubation temperature. However, the effects of such temperature variation on nestling development remain relatively unexplored. To investigate this, we artificially incubated wild blue tit (Cyanistes caeruleus L.) clutches at 35.0°, 36.5°, or 38.0°C for two-thirds of the incubation period. We returned clutches to their original nests before hatching and subsequently recorded nestling growth and resting metabolic rate. The length of the incubation period decreased with temperature, whereas hatching success increased. Nestlings from the lowest incubation temperature group had shorter tarsus lengths at 2 weeks of age, but body mass and wing length were not affected by temperature. In addition, nestlings from the lowest temperature group had a significantly higher resting metabolic rate compared with mid- and high-temperature nestlings, which may partly explain observed size differences between the groups. These findings suggest that nest microclimate can influence nestling phenotype, but whether observed differences carry over to later life-history stages remains unknown. 相似文献
59.
60.
The inactivation of Bacteroides fragilis genes encoding putative RecQ helicases recQ1, recQ2 and recQ3 (ORFs BF638R_3282, BF638R_3781, BF638R_3932) was used to determine whether these proteins are involved in cell survival following metronidazole exposure. The effects of the mutations on growth, cellular morphology and DNA integrity were also evaluated. Mutations in the RecQ DNA helicases caused increased sensitivity to metronidazole, with recQ1, recQ2 and recQ3 mutants being 1.32-fold, 41.88-fold and 23.18-fold more sensitive than the wild type, respectively. There was no difference in cell growth between the recQ1 and recQ3 mutants and the wild type. However, the recQ2 mutant exhibited reduced cell growth, aberrant cell division and increased pleiomorphism, with an increase in filamentous forms and chains of cells being observed using light, fluorescence and electron microscopy. There was no spontaneous accumulation of DNA single- or double-strand breaks in the recQ mutants, as compared with the wild type, during normal cell growth in the absence of metronidazole. Bacteroides fragilis RecQ DNA helicases, therefore, enhance cell survival following metronidazole damage. The abnormal cellular phenotype and growth characteristics of recQ2 mutant cells suggest that this gene, or the downstream gene of the operon in which it occurs, may be involved in cell division. 相似文献