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991.
Sarah?Jesse Jan?KassubekEmail author Hans-Peter?Müller Albert?C?Ludolph Alexander?Unrath 《BMC neurology》2012,12(1):163
Background
Based upon the acquainted loss of dopaminergic neurons in the substantia nigra in Parkinson’s disease (PD), we hypothesised changes in magnetic resonance imaging signal intensities of the basal ganglia to be useful as an additional technical tool in the diagnostic work-up.Methods
Region-of-interest analyses (substantia nigra and globus pallidus internus) of T2-weighted scans were performed in seventy subjects with PD, 170 age- and gender-matched controls and 38 patients with an atypical form of neurodegenerative Parkinsonian syndrome (N?=?11 multisystem atrophy, N?=?22 progressive supranuclear palsy, N?=?5 corticobasal syndrome).Results
In patients with PD, significant changes in signal intensities within the substantia nigra were observed compared to controls at p?<?0.001. For the globus pallidus internus, signal alterations in PD and progressive supranuclear palsy were found to be significant (p?<?0.001) if compared to controls. Furthermore, signal changes of substantia nigra correlated with signal intensities of globus pallidus internus in the ipsilateral hemisphere in both groups. Sensitivity was 86% and specificity was 90% for the combined analysis of substantia nigra and globus pallidus internus in the complete patient sample versus controls.Conclusions
Signal alterations of substantia nigra and globus pallidus internus in routine magnetic resonance imaging were useful to distinguish patients with PD from controls. In addition, signal changes in globus pallidus internus could be used to differentiate progressive supranuclear palsy patients from controls. These analyses have the potential to serve as an additional non-invasive technical tool to support the individual differential diagnosis of PD.992.
Mason P Liang B Li L Fremgen T Murphy E Quinn A Madden SL Biemann HP Wang B Cohen A Komarnitsky S Jancsics K Hirth B Cooper CG Lee E Wilson S Krumbholz R Schmid S Xiang Y Booker M Lillie J Carter K 《PloS one》2012,7(3):e33823
Increased metabolism is a requirement for tumor cell proliferation. To understand the dependence of tumor cells on fatty acid metabolism, we evaluated various nodes of the fatty acid synthesis pathway. Using RNAi we have demonstrated that depletion of fatty-acid synthesis pathway enzymes SCD1, FASN, or ACC1 in HCT116 colon cancer cells results in cytotoxicity that is reversible by addition of exogenous fatty acids. This conditional phenotype is most pronounced when SCD1 is depleted. We used this fatty-acid rescue strategy to characterize several small-molecule inhibitors of fatty acid synthesis, including identification of TOFA as a potent SCD1 inhibitor, representing a previously undescribed activity for this compound. Reference FASN and ACC inhibitors show cytotoxicity that is less pronounced than that of TOFA, and fatty-acid rescue profiles consistent with their proposed enzyme targets. Two reference SCD1 inhibitors show low-nanomolar cytotoxicity that is offset by at least two orders of magnitude by exogenous oleate. One of these inhibitors slows growth of HCT116 xenograft tumors. Our data outline an effective strategy for interrogation of on-mechanism potency and pathway-node-specificity of fatty acid synthesis inhibitors, establish an unambiguous link between fatty acid synthesis and cancer cell survival, and point toward SCD1 as a key target in this pathway. 相似文献
993.
994.
Blume KE Soeroes S Keppeler H Stevanovic S Kretschmer D Rautenberg M Wesselborg S Lauber K 《Journal of immunology (Baltimore, Md. : 1950)》2012,188(1):135-145
Annexin A1 is an intracellular calcium/phospholipid-binding protein that is involved in membrane organization and the regulation of the immune system. It has been attributed an anti-inflammatory role at various control levels, and recently we could show that annexin A1 externalization during secondary necrosis provides an important fail-safe mechanism counteracting inflammatory responses when the timely clearance of apoptotic cells has failed. As such, annexin A1 promotes the engulfment of dying cells and dampens the postphagocytic production of proinflammatory cytokines. In our current follow-up study, we report that exposure of annexin A1 during secondary necrosis coincided with proteolytic processing within its unique N-terminal domain by ADAM10. Most importantly, we demonstrate that the released peptide and culture supernatants of secondary necrotic, annexin A1-externalizing cells induced chemoattraction of monocytes, which was clearly reduced in annexin A1- or ADAM10-knockdown cells. Thus, altogether our findings indicate that annexin A1 externalization and its proteolytic processing into a chemotactic peptide represent final events during apoptosis, which after the transition to secondary necrosis contribute to the recruitment of monocytes and the prevention of inflammation. 相似文献
995.
Arne Jendretzki Ivan Ciklic Rosaura Rodicio Hans-Peter Schmitz Jürgen J. Heinisch 《Molecular genetics and genomics : MGG》2009,282(4):437-451
Cytokinesis in yeast can be achieved by plasma membrane ingression, which is dependent on actomyosin ring constriction. Inn1
presumably couples these processes by interaction with both the plasma membrane and the temporary actomyosin ring component
Hof1. In addition, an actomyosin ring independent cytokinesis pathway exists in yeast. We here identified Cyk3, a key component
of the alternative pathway, as a novel interaction partner of Inn1. The carboxy-terminal proline rich part of Inn1 binds the
SH3 domains of either Cyk3 or Hof1. Strains with truncated proteins lacking either of these SH3 domains do not display any
severe phenotypes, but are synthetically lethal, demonstrating their crucial role in cytokinesis. Overexpression of CYK3 leads to an actomyosin ring independent recruitment of Inn1 to the bud neck, further supporting the significance of this
interaction in vivo. Moreover, overexpression of CYK3 in a myo1 or an iqg1 deletion not only restores viability, but also the recruitment of Inn1 to the bud neck. We propose that Cyk3 is part of an
actomyosin ring independent cytokinesis pathway, which acts as a rescue mechanism to recruit Inn1 to the bud neck. 相似文献
996.
To investigate the role of protein hyperphosphorylation in plant cells, the effect of okadaic acid, a specific inhibitor of protein phosphatases PPI and PP2A, on the general morphology of Arabidopsis thaliana primary roots and the structural-functional characteristics of cortical microtubules in different cell types in all primary root growth zones was studied. It was found that okadaic acid affects microtubule organization in a different manner depending on the type of cells and functional zones of the primary root. Cortical microtubules in the epidermis and cortex cells of the elongation zone proved to be most sensitive to 0.1, 1, and 10 nM okadaic acid which completely depolymerized after inhibitor treatment. In trichoblasts, atrichoblasts of differentiation zone treatment with okadaic acid caused the microtubules stabilization. The treatment with okadaic acid significantly affected the morphology of root hairs, causing their swelling and branching as a result of abnormal microtubule orientation. The results of this study suggest that induction of protein hyperphosphorylation as a result of protein phosphatase inhibition plays a crucial key in microtubule organization in plant cells. 相似文献
997.
A. I. Yemets O. A. Bayer V. V. Radchuk Ya. B. Blume 《Russian Journal of Genetics》2009,45(10):1215-1222
Agrobacterium tumefaciens was used to transform fiber flax with the pBITUBA8 plasmid carrying the mutant α-tubulin gene imparting resistance to dinitroaniline
herbicides and the nptII selective marker gene imparting resistance to kanamycin. The transformants were selected in parallel on media containing
kanamycin and trifluralin (a dinitroaniline herbicide). The transgenic nature of the resultant regenerants resistant to dinitroaniline
herbicides was confirmed by means of Southern blotting and polymerase chain reaction (PCR) analysis using specific probes
for the ntpII gene and the gene of α-tubulin. 相似文献
998.
Axel W. Strittmatter Heiko Liesegang Ralf Rabus Iwona Decker Judith Amann Sönke Andres Anke Henne Wolfgang Florian Fricke Rosa Martinez-Arias Daniela Bartels Alexander Goesmann Lutz Krause Alfred Pühler Hans-Peter Klenk Michael Richter Margarete Schüler Frank Oliver Glöckner Anke Meyerdierks Gerhard Gottschalk Rudolf Amann 《Environmental microbiology》2009,11(5):1038-1055
Sulfate-reducing bacteria (SRB) belonging to the metabolically versatile Desulfobacteriaceae are abundant in marine sediments and contribute to the global carbon cycle by complete oxidation of organic compounds. Desulfobacterium autotrophicum HRM2 is the first member of this ecophysiologically important group with a now available genome sequence. With 5.6 megabasepairs (Mbp) the genome of Db. autotrophicum HRM2 is about 2 Mbp larger than the sequenced genomes of other sulfate reducers (SRB). A high number of genome plasticity elements (> 100 transposon-related genes), several regions of GC discontinuity and a high number of repetitive elements (132 paralogous genes Mbp−1 ) point to a different genome evolution when comparing with Desulfovibrio spp. The metabolic versatility of Db. autotrophicum HRM2 is reflected in the presence of genes for the degradation of a variety of organic compounds including long-chain fatty acids and for the Wood–Ljungdahl pathway, which enables the organism to completely oxidize acetyl-CoA to CO2 but also to grow chemolithoautotrophically. The presence of more than 250 proteins of the sensory/regulatory protein families should enable Db. autotrophicum HRM2 to efficiently adapt to changing environmental conditions. Genes encoding periplasmic or cytoplasmic hydrogenases and formate dehydrogenases have been detected as well as genes for the transmembrane TpII- c 3 , Hme and Rnf complexes. Genes for subunits A, B, C and D as well as for the proposed novel subunits L and F of the heterodisulfide reductases are present. This enzyme is involved in energy conservation in methanoarchaea and it is speculated that it exhibits a similar function in the process of dissimilatory sulfate reduction in Db. autotrophicum HRM2. 相似文献
999.
1000.
Reducing the blood supply of tumors is one modality to combat cancer. Monoclonal antibodies are now established as a key therapeutic approach for a range of diseases. Owing to the ability of antibodies to selectively target endothelial cells within the tumor vasculature, vascular targeting programs have become a mainstay in oncology drug development. However, the antitumor activity of single agent administration of conventional anti-angiogenic compounds is limited and the improvements in patient survival are most prominent in combinations with chemotherapy. Furthermore, prolonged treatment with conventional anti-angiogenic drugs is associated with toxicity and drug resistance. These circumstances provide a strong rationale for novel approaches to enhance the efficacy of mAbs targeting tumor vasculature such as antibody-drug conjugates (ADCs). Here, we review trends in the development of ADCs targeting tumor vasculature with the aim of informing future research and development of this class of therapeutics.Key words: tumor, vasculature, immunotherapy, antibody-drug conjugates, monoclonal antibody, cancer, angiogenesis 相似文献