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61.
Foxp3+ regulatory T cells (Tregs) exhibit plasticity, which dictates their function. Secretion of the inflammatory cytokine IFNγ, together with the acquisition of a T helper 1 (Th1)‐like effector phenotype as observed in cancer, infection, and autoimmune diseases, is associated with loss of Treg suppressor function through an unknown mechanism. Here, we describe the signaling events driving the generation of human Th1‐Tregs. Using a genome‐wide gene expression approach and pathway analysis, we identify the PI3K/AKT/Foxo1/3 signaling cascade as the major pathway involved in IFNγ secretion by human Tregs. Furthermore, we describe the opposing roles of AKT isoforms in Th1‐Treg generation ex vivo. Finally, we employ multiple sclerosis as an in vivo model with increased but functionally defective Th1‐Tregs. We show that the PI3K/AKT/Foxo1/3 pathway is activated in ex vivo‐isolated Tregs from untreated relapsing–remitting MS patients and that blockade of the pathway inhibits IFNγ secretion and restores the immune suppressive function of Tregs. These data define a fundamental pathway regulating the function of human Tregs and suggest a novel treatment paradigm for autoimmune diseases. 相似文献
62.
Yanyu Wang Sarah A. Jenkins Chunfang Gu Ankita Shree Margarita Martinez-Moczygemba Jennifer Herold Marina Botto Rick A. Wetsel Yi Xu 《PLoS pathogens》2016,12(6)
Spores of Bacillus anthracis, the causative agent of anthrax, are known to persist in the host lungs for prolonged periods of time, however the underlying mechanism is poorly understood. In this study, we demonstrated that BclA, a major surface protein of B. anthracis spores, mediated direct binding of complement factor H (CFH) to spores. The surface bound CFH retained its regulatory cofactor activity resulting in C3 degradation and inhibition of downstream complement activation. By comparing results from wild type C57BL/6 mice and complement deficient mice, we further showed that BclA significantly contributed to spore persistence in the mouse lungs and dampened antibody responses to spores in a complement C3-dependent manner. In addition, prior exposure to BclA deletion spores (ΔbclA) provided significant protection against lethal challenges by B. anthracis, whereas the isogenic parent spores did not, indicating that BclA may also impair protective immunity. These results describe for the first time an immune inhibition mechanism of B. anthracis mediated by BclA and CFH that promotes spore persistence in vivo. The findings also suggested an important role of complement in persistent infections and thus have broad implications. 相似文献
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Comparison of the three-dimensional structure of hyperthermophilic and mesophilic β-glycosidases shows differences in secondary
structure composition. The enzymes from hyperthermophilic archaea have a significantly larger number of β-strands arranged
in supernumerary β-sheets compared to mesophilic enzymes from bacteria and other organisms. Amino acid replacements designed
to alter the structure of the supernumerary β-strands were introduced by site directed mutagenesis into the sequence encoding
the β-glycosidase from Sulfolobus solfataricus. Most of the replacements caused almost complete loss of activity but some yielded enzyme variants whose activities were
affected specifically at higher temperatures. Far-UV CD spectra recorded as a function of temperature for both wild type β-glycosidase
and mutant V349G, one of the mutants with reduced activity at higher temperatures, were similar, showing that the protein
structure of the mutant was stable at the highest temperatures assayed. The properties of mutant V349G show a difference between
thermostability (stability of the protein structure at high temperatures) and thermophilicity (optimal activity at high temperatures). 相似文献
66.
Arias-Real Rebeca Gutirrez-Cnovas Cayetano Muoz Isabel Pascoal Cludia Menndez Margarita 《Ecosystems》2022,25(4):780-794
Ecosystems - Investigating the influence of biodiversity on ecosystem functioning over environmental gradients is needed to anticipate ecosystem responses to global change. However, our... 相似文献
67.
Grabeklis Andrey R. Skalny Anatoly V. Skalnaya Anastasia A. Zhegalova Irina V. Notova Svetlana V. Mazaletskaya Anna L. Skalnaya Margarita G. Tinkov Alexey A. 《Biological trace element research》2019,187(1):230-242
Biological Trace Element Research - Chronic exposure to lead causes disruption to energy production mechanisms and tissue damage, in particular through its binding to thiol groups and competition... 相似文献
68.
Margarita Medina‐Romero Andrew O'Reilly‐Nugent Anthony Davidson Jonathan Bray Elizabeth Wandrag Bernd Gruber Angelica Lopez‐Aldana Rakhi Palit Tim Reid Aaron Adamack Rod Pietsch Chris Allen Ralph Mac Nally Richard P. Duncan 《Ecography》2019,42(9):1514-1522
Imperfect detection can bias estimates of site occupancy in ecological surveys but can be corrected by estimating detection probability. Time‐to‐first‐detection (TTD) occupancy models have been proposed as a cost–effective survey method that allows detection probability to be estimated from single site visits. Nevertheless, few studies have validated the performance of occupancy‐detection models by creating a situation where occupancy is known, and model outputs can be compared with the truth. We tested the performance of TTD occupancy models in the face of detection heterogeneity using an experiment based on standard survey methods to monitor koala Phascolarctos cinereus populations in Australia. Known numbers of koala faecal pellets were placed under trees, and observers, uninformed as to which trees had pellets under them, carried out a TTD survey. We fitted five TTD occupancy models to the survey data, each making different assumptions about detectability, to evaluate how well each estimated the true occupancy status. Relative to the truth, all five models produced strongly biased estimates, overestimating detection probability and underestimating the number of occupied trees. Despite this, goodness‐of‐fit tests indicated that some models fitted the data well, with no evidence of model misfit. Hence, TTD occupancy models that appear to perform well with respect to the available data may be performing poorly. The reason for poor model performance was unaccounted for heterogeneity in detection probability, which is known to bias occupancy‐detection models. This poses a problem because unaccounted for heterogeneity could not be detected using goodness‐of‐fit tests and was only revealed because we knew the experimentally determined outcome. A challenge for occupancy‐detection models is to find ways to identify and mitigate the impacts of unobserved heterogeneity, which could unknowingly bias many models. 相似文献
69.
Margarita Kirkova Elina Tzvetanova Stefani Vircheva Rositsa Zamfirova Beata Grygier Marta Kubera 《Cell biochemistry and function》2010,28(6):497-502
In vivo effects of the antidepressant fluoxetine on spleen antioxidant status of C57BL/6 mice were studied using a melanoma experimental model. After a 14‐day treatment with fluoxetine (10 mg kg?1 day?1, i.p.), the endogenous antioxidant non‐enzyme (glutathione) and enzyme (superoxide dismutase (SOD) and glutathione peroxidase (GPx)) defense systems in spleen of healthy animals were not changed; the lipid peroxidation (LP) was also unchanged. When B16F10 melanoma cells were introduced in C57BL/6 mice 2 h before fluoxetine treatment, a drug‐protective effect against the melanoma‐induced oxidative changes (increased LP and decreased total glutathione (GSH)‐level, as well as antioxidant enzyme activities) in spleen was observed. Fluoxetine dose‐dependently reduced the amounts of free oxygen radicals (hydroxyl and superoxide anion radicals), generated in chemical systems. Taken together, the present results suggest that fluoxetine, acting as antioxidant, prevents from melanoma‐induced oxidative changes in mice spleen. Copyright © 2010 John Wiley & Sons, Ltd. 相似文献
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