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101.
Lucas K. Smith Evgenia Verovskaya Gregor Bieri Alana M. Horowitz Saskia N. I. von Ungern‐Sternberg Karin Lin Peter Seizer Emmanuelle Passegu Saul A. Villeda 《Aging cell》2020,19(8)
The aged systemic milieu promotes cellular and cognitive impairments in the hippocampus. Here, we report that aging of the hematopoietic system directly contributes to the pro‐aging effects of old blood on cognition. Using a heterochronic hematopoietic stem cell (HSC) transplantation model (in which the blood of young mice is reconstituted with old HSCs), we find that exposure to an old hematopoietic system inhibits hippocampal neurogenesis, decreases synaptic marker expression, and impairs cognition. We identify a number of factors elevated in the blood of young mice reconstituted with old HSCs, of which cyclophilin A (CyPA) acts as a pro‐aging factor. Increased systemic levels of CyPA impair cognition in young mice, while inhibition of CyPA in aged mice improves cognition. Together, these data identify age‐related changes in the hematopoietic system as drivers of hippocampal aging. 相似文献
102.
Maria Carolina Florian Hanna Leins Michael Gobs Yang Han Gina Marka Karin Soller Angelika Vollmer Vadim Sakk Kalpana J. Nattamai Ahmad Rayes Xueheng Zhao Kenneth Setchell Medhanie Mulaw Wolfgang Wagner Yi Zheng Hartmut Geiger 《Aging cell》2020,19(9)
Cdc42 is a small RhoGTPase regulating multiple functions in eukaryotic cells. The activity of Cdc42 is significantly elevated in several tissues of aged mice, while the Cdc42 gain‐of‐activity mouse model presents with a premature aging‐like phenotype and with decreased lifespan. These data suggest a causal connection between elevated activity of Cdc42, aging, and reduced lifespan. Here, we demonstrate that systemic treatment of aged (75‐week‐old) female C57BL/6 mice with a Cdc42 activity‐specific inhibitor (CASIN) for 4 consecutive days significantly extends average and maximum lifespan. Moreover, aged CASIN‐treated animals displayed a youthful level of the aging‐associated cytokines IL‐1β, IL‐1α, and INFγ in serum and a significantly younger epigenetic clock as based on DNA methylation levels in blood cells. Overall, our data show that systemic administration of CASIN to reduce Cdc42 activity in aged mice extends murine lifespan. 相似文献
103.
Felde Vivian A. Flantua Suzette G. A. Jenks Cathy R. Benito Blas M. de Beaulieu Jacques-Louis Kuneš Petr Magri Donatella Nalepka Dorota Risebrobakken Bjørg ter Braak Cajo J. F. Allen Judy R. M. Granoszewski Wojciech Helmens Karin F. Huntley Brian Kondratienė Ona Kalniņa Laimdota Kupryjanowicz Mirosława Malkiewicz Małgorzata Milner Alice M. Nita Małgorzata Noryśkiewicz Bożena Pidek Irena A. Reille Maurice Salonen J. Sakari Šeirienė Vaida Winter Hanna Tzedakis Polychronis C. Birks H. John B. 《Vegetation History and Archaeobotany》2020,29(1):101-109
Vegetation History and Archaeobotany - The Eemian interglacial represents a natural experiment on how past vegetation with negligible human impact responded to amplified temperature changes... 相似文献
104.
Wenfei Ding Hui Yin Tan Jia Xiang Zhang Luke A. Wilczek Karin R. Hsieh Jeffrey A. Mulkin Piero R. Bianco 《Protein science : a publication of the Protein Society》2020,29(5):1211-1227
The Escherichia coli single‐strand DNA binding protein (SSB) is essential to viability where it functions to regulate SSB interactome function. Here it binds to single‐stranded DNA and to target proteins that comprise the interactome. The region of SSB that links these two essential protein functions is the intrinsically disordered linker. Key to linker function is the presence of three, conserved PXXP motifs that mediate binding to oligosaccharide‐oligonucleotide binding folds (OB‐fold) present in SSB and its interactome partners. Not surprisingly, partner OB‐fold deletions eliminate SSB binding. Furthermore, single point mutations in either the PXXP motifs or, in the RecG OB‐fold, obliterate SSB binding. The data also demonstrate that, and in contrast to the view currently held in the field, the C‐terminal acidic tip of SSB is not required for interactome partner binding. Instead, we propose the tip has two roles. First, and consistent with the proposal of Dixon, to regulate the structure of the C‐terminal domain in a biologically active conformation that prevents linkers from binding to SSB OB‐folds until this interaction is required. Second, as a secondary binding domain. Finally, as OB‐folds are present in SSB and many of its partners, we present the SSB interactome as the first family of OB‐fold genome guardians identified in prokaryotes. 相似文献
105.
Jrg Bckelmann Karin Tremetsberger Kateina umberov Gudrun Kohl Heinrich Grausgruber Karl‐Georg Bernhardt 《Ecology and evolution》2020,10(8):3620-3635
Many ephemeral mudflat species, which rely on a soil seed bank to build up the next generation, are endangered in their natural habitat due to the widespread regulation of rivers. The aim of the present study was to elucidate the role of the soil seed bank and dispersal for the maintenance of genetic diversity in populations of near‐natural river habitats and anthropogenic habitats created by traditional fish farming practices using Cyperus fuscus as a model. Using microsatellite markers, we found no difference in genetic diversity levels between soil seed bank and above‐ground population and only moderate differentiation between the two fractions. One possible interpretation is the difference in short‐term selection during germination under specific conditions (glasshouse versus field) resulting in an ecological filtering of genotypes out of the reservoir in the soil. River populations harbored significantly more genetic diversity than populations from the anthropogenic pond types. We suggest that altered levels and patterns of dispersal together with stronger selection pressures and historical bottlenecks in anthropogenic habitats are responsible for the observed reduction in genetic diversity. Dispersal is also supposed to largely prohibit genetic structure across Europe, although there is a gradient in private allelic richness from southern Europe (high values) to northern, especially north‐western, Europe (low values), which probably relates to postglacial expansion out of southern and/or eastern refugia. 相似文献
106.
Carl Rafferty Kjell Johnson Jim O'Mahony Barbara Burgoyne Rosemary Rea Karin M. Balss 《Biotechnology progress》2020,36(4):e2977
The Food and Drug Administration (FDA) initiative of Process Analytical Technology (PAT) encourages the monitoring of biopharmaceutical manufacturing processes by innovative solutions. Raman spectroscopy and the chemometric modeling tool partial least squares (PLS) have been applied to this aim for monitoring cell culture process variables. This study compares the chemometric modeling methods of Support Vector Machine radial (SVMr), Random Forests (RF), and Cubist to the commonly used linear PLS model for predicting cell culture components—glucose, lactate, and ammonia. This research is performed to assess whether the use of PLS as standard practice is justified for chemometric modeling of Raman spectroscopy and cell culture data. Model development data from five small-scale bioreactors (2 × 1 L and 3 × 5 L) using two Chinese hamster ovary (CHO) cell lines were used to predict against a manufacturing scale bioreactor (2,000 L). Analysis demonstrated that Cubist predictive models were better for average performance over PLS, SVMr, and RF for glucose, lactate, and ammonia. The root mean square error of prediction (RMSEP) of Cubist modeling was acceptable for the process concentration ranges of glucose (1.437 mM), lactate (2.0 mM), and ammonia (0.819 mM). Interpretation of variable importance (VI) results theorizes the potential advantages of Cubist modeling in avoiding interference of Raman spectral peaks. Predictors/Raman wavenumbers (cm−1) of interest for individual variables are X1139–X1141 for glucose, X846–X849 for lactate, and X2941–X2943 for ammonia. These results demonstrate that other beneficial chemometric models are available for use in monitoring cell culture with Raman spectroscopy. 相似文献
107.
Temmink Ralph J. M. Dorenbosch Martijn Lamers Leon P. M. Smolders Alfons J. P. Rip Winnie Lengkeek Wouter Didderen Karin Fivash Gregory S. Bouma Tjeerd J. van der Heide Tjisse 《Hydrobiologia》2021,848(17):3987-3999
Hydrobiologia - Aquatic ecosystems provide vital services, and macrophytes play a critical role in their functioning. Conceptual models indicate that in shallow lakes, plants with different growth... 相似文献
108.
Pratiti Bhadra Lalitha Yadhanapudi Karin Rmisch Volkhard Helms 《PLoS computational biology》2021,17(3)
The Sec complex catalyzes the translocation of proteins of the secretory pathway into the endoplasmic reticulum and the integration of membrane proteins into the endoplasmic reticulum membrane. Some substrate peptides require the presence and involvement of accessory proteins such as Sec63. Recently, a structure of the Sec complex from Saccharomyces cerevisiae, consisting of the Sec61 channel and the Sec62, Sec63, Sec71 and Sec72 proteins was determined by cryo-electron microscopy (cryo-EM). Here, we show by co-precipitation that the Sec61 channel subunit Sbh1 is not required for formation of stable Sec63-Sec61 contacts. Molecular dynamics simulations started from the cryo-EM conformation of Sec61 bound to Sec63 and of unbound Sec61 revealed how Sec63 affects the conformation of Sec61 lateral gate, plug, pore region and pore ring diameter via three intermolecular contact regions. Molecular docking of SRP-dependent vs. SRP-independent signal peptide chains into the Sec61 channel showed that the pore regions affected by presence/absence of Sec63 play a crucial role in positioning the signal anchors of SRP-dependent substrates nearby the lateral gate. 相似文献
109.
β-Glucan process-related impurities can be introduced into biopharmaceutical products via upstream or downstream processing or via excipients. This study obtained a comprehensive process-mapping dataset for five monoclonal antibodies to assess β-glucan introduction and clearance during development and production runs at various scales. Overall, 198 data points were available for analysis. The greatest β-glucan concentrations were found in the depth-filtration filtrate (37–2,745 pg/ml). Load volume correlated with β-glucan concentration in the filtrate, whereas flush volume was of secondary importance. Cation-exchange chromatography significantly cleared β-glucans. Furthermore, β-glucan leaching from the Planova 20N virus removal filter was reduced by increasing the flush volume (1 vs. 10 L/m2). β-glucan concentrations after filter flush with 10 L/m2 were consistently <10 pg/ml. No or only limited β-glucan clearance was attained via ultrafiltration/diafiltration (UF/DF). However, during the first run with monoclonal antibody (mAb) 4, β-glucan concentration in the UF/DF retentate was 10.8 pg/mg, potentially due to β-glucan leaching from the first run with a regenerated cellulose membrane. Overall, β-glucan levels in the final mAb drug substance were 1–12 pg/mg. Assuming high doses of 1,000–5,000 mg, a β-glucan contamination at 20 pg/mg would translate to 20–100 ng/dose, which is below the previously suggested threshold for product safety (≤500 ng/dose). 相似文献
110.
Karin Müller Keri L.H. Carpenter Iain R. Challis Jeremy N. Skepper Mark J. Arends 《Free radical research》2013,47(7):791-802
Epidemiologically, a high-carotenoid intake via a fruit- and vegetable-rich diet is associated with a decreased risk of various forms of cancer. The mechanisms by which carotenoids exert this protective effect are controversial. In this study, we examined the potency of a range of carotenoids commonly found in human plasma to induce apoptosis in Jurkat E6.1 malignant T-lymphoblast cells. At a concentration of 20 w M, the order of potency to induce apoptosis after 24 h was: g -carotene > lycopene > lutein> g -cryptoxanthin=zeaxanthin. Canthaxanthin failed to induce apoptosis under these conditions. g -Carotene induced apoptosis in a time- and concentration-dependent manner with a lowest effective concentration of about 3 w M. Pre-conditioning of g -carotene for 72 h destroyed its pro-apoptotic activity almost completely, whereas degradation for 6 h or less did not, indicating that either g -carotene itself and/or an early degradation product of g -carotene are the death-inducing compounds. Apoptosis induced by g -carotene was characterized by chromatin condensation and nuclear fragmentation, DNA degradation, PARP cleavage and caspase-3 activation. The antioxidant BO-653 inhibited the degradation of g -carotene in vitro and significantly increased its cytotoxicity, indicating that a pro-oxidant effect of g -carotene is unlikely to cause its pro-apoptotic activity. The induction of apoptosis in transformed cells by carotenoids may explain their protective effect against cancer formation in humans. Possible pathways for induction of apoptosis by carotenoids are discussed. 相似文献