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91.
Kelly M. Adams Valsamma Abraham Daniel Spielman Jay K. Kolls Ronald C. Rubenstein Gregory E. Conner Noam A. Cohen James L. Kreindler 《PloS one》2014,9(8)
The epithelium plays an active role in the response to inhaled pathogens in part by responding to signals from the immune system. Epithelial responses may include changes in chemokine expression, increased mucin production and antimicrobial peptide secretion, and changes in ion transport. We previously demonstrated that interleukin-17A (IL-17A), which is critical for lung host defense against extracellular bacteria, significantly raised airway surface pH in vitro, a finding that is common to a number of inflammatory diseases. Using microarray analysis of normal human bronchial epithelial (HBE) cells treated with IL-17A, we identified the electroneutral chloride-bicarbonate exchanger Pendrin (SLC26A4) as a potential mediator of this effect. These data were verified by real-time, quantitative PCR that demonstrated a time-dependent increase in Pendrin mRNA expression in HBE cells treated with IL-17A up to 48 h. Using immunoblotting and immunofluorescence, we confirmed that Pendrin protein expression is increased in IL-17 treated HBE cells and that it is primarily localized to the mucosal surface of the cells. Functional studies using live-cell fluorescence to measure intracellular pH demonstrated that IL-17A induced chloride-bicarbonate exchange in HBE cells that was not present in the absence of IL-17A. Furthermore, HBE cells treated with short interfering RNA against Pendrin showed substantially reduced chloride-bicarbonate exchange. These data suggest that Pendrin is part of IL-17A-dependent epithelial changes and that Pendrin may therefore be a therapeutic target in IL-17A-dependent lung disease. 相似文献
92.
Wai Shing Tang Gabriel Monteiro da Silva Henry Kirveslahti Erin Skeens Bibo Feng Timothy Sudijono Kevin K. Yang Sayan Mukherjee Brenda Rubenstein Lorin Crawford 《PLoS computational biology》2022,18(5)
Identifying structural differences among proteins can be a non-trivial task. When contrasting ensembles of protein structures obtained from molecular dynamics simulations, biologically-relevant features can be easily overshadowed by spurious fluctuations. Here, we present SINATRA Pro, a computational pipeline designed to robustly identify topological differences between two sets of protein structures. Algorithmically, SINATRA Pro works by first taking in the 3D atomic coordinates for each protein snapshot and summarizing them according to their underlying topology. Statistically significant topological features are then projected back onto a user-selected representative protein structure, thus facilitating the visual identification of biophysical signatures of different protein ensembles. We assess the ability of SINATRA Pro to detect minute conformational changes in five independent protein systems of varying complexities. In all test cases, SINATRA Pro identifies known structural features that have been validated by previous experimental and computational studies, as well as novel features that are also likely to be biologically-relevant according to the literature. These results highlight SINATRA Pro as a promising method for facilitating the non-trivial task of pattern recognition in trajectories resulting from molecular dynamics simulations, with substantially increased resolution. 相似文献
93.
Kristina H. Schmidt Emilie Viebranz Lillian Doerfler Christina Lester Aaron Rubenstein 《PloS one》2010,5(8)
Genome instability, associated with chromosome breakage syndromes and most human
cancers, is still poorly understood. In the yeast Saccharomyces
cerevisiae, numerous genes with roles in the preservation of genome
integrity have been identified. DNA-damage-checkpoint-deficient yeast cells that
lack Sgs1, a RecQ-like DNA helicase related to the human
Bloom''s-syndrome-associated helicase BLM, show an increased rate of
genome instability, and we have previously shown that they accumulate recurring
chromosomal translocations between three similar genes, CAN1,
LYP1 and ALP1. Here, the chromosomal
location, copy number and sequence similarity of the translocation targets
ALP1 and LYP1 were altered to gain insight
into the formation of complex translocations. Among 844 clones with chromosomal
rearrangements, 93 with various types of simple and complex translocations
involving CAN1, LYP1 and ALP1
were identified. Breakpoint sequencing and mapping showed that the formation of
complex translocation types is strictly dependent on the location of the
initiating DNA break and revealed that complex translocations arise via a
combination of interchromosomal translocation and template-switching, as well as
from unstable dicentric intermediates. Template-switching occurred between
sequences on the same chromosome, but was inhibited if the genes were
transferred to different chromosomes. Unstable dicentric translocations
continuously gave rise to clones with multiple translocations in various
combinations, reminiscent of intratumor heterogeneity in human cancers. Base
substitutions and evidence of DNA slippage near rearrangement breakpoints
revealed that translocation formation can be accompanied by point mutations, and
their presence in different translocation types within the same clone provides
evidence that some of the different translocation types are derived from each
other rather than being formed de novo. These findings provide
insight into eukaryotic genome instability, especially the formation of
translocations and the sources of intraclonal heterogeneity, both of which are
often associated with human cancers. 相似文献
94.
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97.
Cuihua Wang Sofia Barluenga Girish K. Koripelly Jean-Gonzague Fontaine Ruihong Chen Jin-Chen Yu Xiaodong Shen John C. Chabala James V. Heck Allan Rubenstein Nicolas Winssinger 《Bioorganic & medicinal chemistry letters》2009,19(14):3836-3840
Pochoximes are potent inhibitors of heat shock protein 90 (HSP90) based on the radicicol pharmacophores. Herein we present a pharmacokinetics and pharmacodynamics evaluation of this compound series as well as a phosphate prodrug strategy to facilitate formulation and improve oral bioavailability. 相似文献
98.
Summary During contests animals typically exchange information about fighting ability. Among feral horses these signals involve olfactory or acoustical elements and each type can effectively terminate contests before physical contact becomes necessary. Dung transplant experiments show that for stallions, irrespective of rank, olfactory signals such as dung sniffing encode information about familiarity suggesting that such signals can be used as signatures. As such they can provide indirect information about fighting ability as long as opponents associate identity with past performance. Play-back experiments, however, show that vocalizations, such as squeals, directly provide information about status regardless of stallion familiarity. Sonographs reveal that squeals of dominants are longer than those of subordinates and that only those of dominants have at their onset high-frequency components. 相似文献
99.
The selective regulation of Gs (long and short forms), Gi's (1, 2, and 3), and Go by the beta-adrenergic receptor was assessed quantitatively after coreconstitution of purified receptor, purified G-protein beta gamma subunits, and individual recombinant G-protein alpha subunits that were expressed in and purified from Escherichia coli. Receptor and beta gamma subunits were incorporated into phospholipid vesicles, and the alpha subunits bound to the vesicles stoichiometrically with respect to beta gamma. Efficient regulation of alpha subunit by receptor required the presence of beta gamma. Regulation of G proteins was measured according to the stimulation of the initial rate of GTP gamma S binding, steady-state GTPase activity, and equilibrium GDP/GDP exchange. The assays yielded qualitatively similar results. GDP/GDP exchange was a first-order reaction for each subunit. The rate constant increased linearly with the concentration of agonist-liganded receptor, and the dependence of the rate constant on receptor concentration was a reproducible measurement of the efficiency with which receptor regulated each G protein. Reconstituted alpha s (long or short form) was stimulated by receptor to approximately the extent described previously for natural Gs. Both alpha i,1 and alpha i,3 were regulated with 25-33% of that efficiency. Stimulation of alpha o and alpha i,2 was weak, and stimulation of alpha o was barely detectable over its high basal exchange rate. Reduction of the receptor with dithiothreitol increased the exchange rates for all G proteins but did not alter the relative selectivity of the receptor. 相似文献
100.
Mutualistic acacia ants exhibit reduced aggression and more frequent off‐tree movements near termite mounds
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Lucas P. Henry Christopher K. Tokita Mayank Misra Avery B. Forrow Daniel I. Rubenstein 《Biotropica》2018,50(4):559-562
In many ant–plant mutualisms, ants establish colonies in hollow thorns, leaf pouches, or other specialized structures on their host plants, which they then defend from herbivores. Resource heterogeneity could affect the maintenance of these mutualisms if it leads to one or both partners altering their investment in the interaction. Such a phenomenon may be especially pertinent to the Acacia–ant mutualism found in East African savannas, where termite mounds have a profound effect on the spatial structuring of resources used by both plants and ants. Here, we examined whether the proximity to termite mounds of Acacia drepanolobium trees is associated with variation in the behavior of one of their ant associates, Crematogaster nigriceps. We found that ant colonies near termite mounds had decreased aggressive responses to simulated herbivory as well as increased off‐tree movement. We hypothesize that these changes are the result of resident ant colonies near termite mounds shifting investment from defense of their host plant to foraging for nearby resources. 相似文献