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91.
Niels Andreasen Monica Simeoni Henrik Ostlund Pia I. Lisjo Tormod Fladby Amy E. Loercher Gerard J. Byrne Frances Murray Paul T. Scott-Stevens Anders Wallin Yinghua Y. Zhang Lena H. Bronge Henrik Zetterberg Agneta K. Nordberg Astrid J. Yeo Shahid A. Khan Jan Hilpert Prafull C. Mistry 《PloS one》2015,10(3)
Objective
To assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of the Fc-inactivated anti-β amyloid (Aβ) monoclonal antibody (mAb) GSK933776 in patients with mild Alzheimer’s disease (AD) or mild cognitive impairment (MCI).Methods
This was a two-part, single blind, placebo-controlled, first-time-in-human (FTIH) study of single (n = 18) and repeat dose (n = 32) intravenous GSK933776 0.001–6 mg/kg (ClinicalTrials.gov: NCT00459550). Additional safety data from an open-label, uncontrolled, single dose study of intravenous GSK933776 1–6 mg/kg (n = 18) are included (ClinicalTrials.gov: NCT01424436).Results
There were no cases of amyloid-related imaging abnormalities-edema (ARIA-E) or –hemorrhage (ARIA-H) after GSK933776 administration in both studies. Three patients across the two studies developed anti-GSK933776 antibodies. Plasma GSK933776 half-life (t1/2) was 10–15 days after repeat dosing. After each of three administrations of GSK933776, plasma levels of total Aβ42 and Aβ increased whereas plasma levels of free Aβ decreased dose dependently; no changes were observed for placebo. For total Aβ42 the peak:trough ratio was ≤2 at doses ≥3 mg/kg; for total Aβ the ratio was ≤2 at 6 mg/kg. CSF concentrations of Aβ showed increases from baseline to week 12 for Aβ X–38 (week 12:baseline ratio: 1.65; 95%CI: 1.38, 1.93) and Aβ X–42 (week 12:baseline ratio: 1.18; 95%CI: 1.06, 1.30) for values pooled across doses.Conclusion
In this FTIH study the Fc-inactivated anti-Aβ mAb GSK933776 engaged its target in plasma and CSF without causing brain ARIA-E/H in patients with mild AD or MCI.Trial Registration
ClinicalTrials.gov NCT00459550 相似文献92.
Microtubule plus-end conformations and dynamics in the periphery of interphase mouse fibroblasts 下载免费PDF全文
Zovko S Abrahams JP Koster AJ Galjart N Mommaas AM 《Molecular biology of the cell》2008,19(7):3138-3146
The plus ends of microtubules (MTs) alternate between phases of growth, pause, and shrinkage, a process called "dynamic instability." Cryo-EM of in vitro-assembled MTs indicates that the dynamic state of the plus end corresponds with a particular MT plus-end conformation. Frayed ("ram's horn like"), blunt, and sheet conformations are associated with shrinking, pausing, and elongating plus ends, respectively. A number of new conformations have recently been found in situ but their dynamic states remained to be confirmed. Here, we investigated the dynamics of MT plus ends in the peripheral area of interphase mouse fibroblasts (3T3s) using electron microscopical and tomographical analysis of cryo-fixed, freeze-substituted, and flat-embedded sections. We identified nine morphologically distinct plus-end conformations. The frequency of these conformations correlates with their proximity to the cell border, indicating that the dynamic status of a plus end is influenced by features present in the periphery. Shifting dynamic instability toward depolymerization with nocodazole enabled us to address the dynamic status of these conformations. We suggest a new transition path from growth to shrinkage via the so-called sheet-frayed and flared ends, and we present a kinetic model that describes the chronology of events taking place in nocodazole-induced MT depolymerization. 相似文献
93.
Ubiquitylation of BAG-1 suggests a novel regulatory mechanism during the sorting of chaperone substrates to the proteasome 总被引:5,自引:0,他引:5
Alberti S Demand J Esser C Emmerich N Schild H Hohfeld J 《The Journal of biological chemistry》2002,277(48):45920-45927
BAG-1 is a ubiquitin domain protein that links the molecular chaperones Hsc70 and Hsp70 to the proteasome. During proteasomal sorting BAG-1 can cooperate with another co-chaperone, the carboxyl terminus of Hsc70-interacting protein CHIP. CHIP was recently identified as a Hsp70- and Hsp90-associated ubiquitin ligase that labels chaperone-presented proteins with the degradation marker ubiquitin. Here we show that BAG-1 itself is a substrate of the CHIP ubiquitin ligase in vitro and in vivo. CHIP mediates attachment of ubiquitin moieties to BAG-1 in conjunction with ubiquitin-conjugating enzymes of the Ubc4/5 family. Ubiquitylation of BAG-1 is strongly stimulated when a ternary Hsp70.BAG-1.CHIP complex is formed. Complex formation results in the attachment of an atypical polyubiquitin chain to BAG-1, in which the individual ubiquitin moieties are linked through lysine 11. The noncanonical polyubiquitin chain does not induce the degradation of BAG-1, but it stimulates a degradation-independent association of the co-chaperone with the proteasome. Remarkably, this stimulating activity depends on the simultaneous presentation of the integrated ubiquitin-like domain of BAG-1. Our data thus reveal a cooperative recognition of sorting signals at the proteolytic complex. Attachment of polyubiquitin chains to delivery factors may represent a novel mechanism to regulate protein sorting to the proteasome. 相似文献
94.
Mette Nyegaard Nanna D. Rendtorff Morten S. Nielsen Thomas J. Corydon Ditte Demontis Anna Starnawska Anne Hedemand Annalisa Buniello Francesco Niola Michael T. Overgaard Suzanne M. Leal Wasim Ahmad Friedrik P. Wikman Kirsten B. Petersen Dorthe G. Crüger Jaap Oostrik Hannie Kremer Niels Tommerup Morten Fr?din Karen P. Steel Lisbeth Tranebj?rg Anders D. B?rglum 《PLoS genetics》2015,11(7)
95.
In order to elucidate the phylogeny and evolutionary history of the Bacillariaceae we conducted a phylogenetic analysis of 42 species (sequences were determined from more than two strains of many of the Pseudo-nitzschia species) based on the first 872 base pairs of nuclear-encoded large subunit (LSU) rDNA, which include some of the most variable domains. Four araphid genera were used as the outgroup in maximum likelihood, parsimony and distance analyses. The phylogenetic inferences revealed the Bacillariaceae as monophyletic (bootstrap support ≥90%). A clade comprising Pseudo-nitzschia, Fragilariopsis and Nitzschia americana (clade A) was supported by high bootstrap values (≥94%) and agreed with the morphological features revealed by electron microscopy. Data for 29 taxa indicate a subdivision of clade A, one clade comprising Pseudo-nitzschia species, a second clade consisting of Pseudo-nitzschia species and Nitzschia americana, and a third clade comprising Fragilariopsis species. Pseudo-nitzschia as presently defined is paraphyletic and emendation of the genus is probably needed. The analyses suggested that Nitzschia is not monophyletic, as expected from the great morphological diversity within the genus. A cluster characterized by possession of detailed ornamentation on the frustule is indicated. Eighteen taxa (16 within the Bacillariaceae) were tested for production of domoic acid, a neurotoxic amino acid. Only P. australis, P. multiseries and P. seriata produced domoic acid, and these clustered together in all analyses. Since Nitzschia navis-varingica also produces domoic acid, but is distantly related to the cluster comprising the Pseudo-nitzschia domoic acid producers, it is most parsimonious to suggest that the ability of species in the Bacillariaceae to produce domoic acid has evolved at least twice. 相似文献
96.
Steen Pedersen Solveig V. Reeh Jack Parker Robert J. Watson James D. Friesen Niels P. Fiil 《Molecular & general genetics : MGG》1976,144(3):339-343
Summary The presence of EF-Tu, RNA polymerase subunit , and EF-G on the dfus-3 genome and EF-Tu, ribosomal proteins L7/L12, and RNA polymerase subunit on the drif
d
18 genome has been confirmed using a two-dimensional gel electrophoresis technique sensitive to changes in isoelectric point and molecular weight. In this system two EF-Tu gene products could not be resolved. Following infection of ultraviolet light-irradiated Escherichia coli with either dfus-3 or drif
d
18, the EF-Tu gene, tufA, near 65 minutes on the genetic map is expressed as 3–4 copies per EF-G molecule. The EF-Tu gene, tufB, near 79 minutes on the genetic map, is expressed at about one-third of this rate. is expressed as 1 copy per EF-G molecule, as 0.14 per EF-G molecule and L7/L12 as 2.5 per EF-G. These figures compare well with the relative amounts found in exponentially-growing cells, in which the ratio of EF-Tu to EF-G is approximately 5. Almost 90% of the total number of proteins (calculated on a molecular weight basis) which theoretically can be encoded on the drif
d
18 have been identified on the two-dimensional gel. 相似文献
97.
High pressure liquid chromatography (HPLC) using 4′ × 1/8″ columns of a pellicular silica support (Corasil-II) allows identification of prostaglandins diastereomers based on their characteristic retention relative to a standard, PGE2 in this study. Surprisingly this simple method allows separation of PGE2, PGE1, and PGEo (dihydro-PGE1) or PGF2α, PGF1α, and PGFoα without resort to silver nitrate impregnated stationary phases. Even more subtle distinctions such as that between 13,14-dihydro-PGF2α, PGF1α and 5,6-
-PGF2α are possible by HPLC. The differential refractometer detector used throughout can also be used for quantitation. This is illustrated by a study of the relative rates of degradation of natural PGF2α (an oil at the temperature employed, 41°C) and racemic PGF2α (mp. 63°) on exposure to air. 相似文献
98.
Mice that lack astrotactin have slowed neuronal migration 总被引:8,自引:0,他引:8
The cortical regions of the brain are laminated as a result of directed migration of precursor cells along glia during development. Previously, we have used an assay system to identify astrotactin as a neuronal ligand for migration on glial fibers. To examine the function of astrotactin in vivo, we generated a null mutation by targeted gene disruption. The cerebella of astrotactin null mice are approximately 10% smaller than wild type. In vitro and in vivo cerebellar granule cell assays show a decrease in neuron-glial binding, a reduction in migration rates and abnormal development of Purkinje cells. Consequences of this are poorer balance and coordination. Thus, astrotactin functions in migration along glial processes in vivo, a process required for generating laminar structures and for the development of synaptic partner systems. 相似文献
99.
Sofia J. van Moorsel Marc W. Schmid Niels C. A. M. Wagemaker Thomas van Gurp Bernhard Schmid Philippine Vergeer 《Molecular ecology》2019,28(17):4097-4117
In long‐term grassland experiments, positive biodiversity effects on plant productivity commonly increase with time. Subsequent glasshouse experiments showed that these strengthened positive biodiversity effects persist not only in the local environment but also when plants are transferred into a common environment. Thus, we hypothesized that community diversity had acted as a selective agent, resulting in the emergence of plant monoculture and mixture types with differing genetic composition. To test our hypothesis, we grew offspring from plants that were grown for eleven years in monoculture or mixture environments in a biodiversity experiment (Jena Experiment) under controlled glasshouse conditions in monocultures or two‐species mixtures. We used epiGBS, a genotyping‐by‐sequencing approach combined with bisulphite conversion, to provide integrative genetic and epigenetic (i.e., DNA methylation) data. We observed significant divergence in genetic and DNA methylation data according to selection history in three out of five perennial grassland species, namely Galium mollugo, Prunella vulgaris and Veronica chamaedrys, with DNA methylation differences mostly reflecting the genetic differences. In addition, current diversity levels in the glasshouse had weak effects on epigenetic variation. However, given the limited genome coverage of the reference‐free bisulphite method epiGBS, it remains unclear how much of the differences in DNA methylation was independent of underlying genetic differences. Our results thus suggest that selection of genetic variants, and possibly epigenetic variants, caused the rapid emergence of monoculture and mixture types within plant species in the Jena Experiment. 相似文献
100.
Madsen DH Ingvarsen S Jürgensen HJ Melander MC Kjøller L Moyer A Honoré C Madsen CA Garred P Burgdorf S Bugge TH Behrendt N Engelholm LH 《The Journal of biological chemistry》2011,286(30):26996-27010
The degradation of collagens, the most abundant proteins of the extracellular matrix, is involved in numerous physiological and pathological conditions including cancer invasion. An important turnover pathway involves cellular internalization and degradation of large, soluble collagen fragments, generated by initial cleavage of the insoluble collagen fibers. We have previously observed that in primary mouse fibroblasts, this endocytosis of collagen fragments is dependent on the receptor urokinase plasminogen activator receptor-associated protein (uPARAP)/Endo180. Others have identified additional mechanisms of collagen uptake, with different associated receptors, in other cell types. These receptors include β1-integrins, being responsible for collagen phagocytosis, and the mannose receptor. We have now utilized a newly developed monoclonal antibody against uPARAP/Endo180, which down-regulates the receptor protein level on treated cells, to examine the role of uPARAP/Endo180 as a mediator of collagen internalization by a wide range of cultured cell types. With the exception of macrophages, all cells that proved capable of efficient collagen internalization were of mesenchymal origin and all of these utilized uPARAP/Endo180 for their collagen uptake process. Macrophages internalized collagen in a process mediated by the mannose receptor, a protein belonging to the same protein family as uPARAP/Endo180. β1-Integrins were found not to be involved in the endocytosis of soluble collagen, irrespectively of whether this was mediated by uPARAP/Endo180 or the mannose receptor. This further distinguishes these pathways from the phagocytic uptake of particulate collagen. 相似文献