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René Röder Petra Henklein Hardy Weißhoff Clemens Mügge Michael Pätzel Ulrich Schubert Louis A. Carpino Peter Henklein 《Journal of peptide science》2010,16(1):65-70
To prevent aspartimide formation and related side products in Asp‐Xaa, particularly Asp‐Gly‐containing peptides, usually the 2‐hydroxy‐4‐methoxybenzyl (Hmb) backbone amide protection is applied for peptide synthesis according to the Fmoc‐protocols. In the present study, the usefulness of the recently proposed acid‐labile dicyclopropylmethyl (Dcpm) protectant was analyzed. Despite the significant steric hindrance of this bulky group, N‐terminal H‐(Dcpm)Gly‐peptides are quantitatively acylated by potent acylating agents, and alternatively the dipeptide Fmoc‐Asp(OtBu)‐(Dcpm)Gly‐OH derivative can be used as a building block. In contrast to the Hmb group, Dcpm is inert toward acylations, but is readily removed in the acid deprotection and resin‐cleavage step. Copyright © 2009 European Peptide Society and John Wiley & Sons, Ltd. 相似文献
125.
Jinho Kim Daniel J. Amante Jennifer P. Moody Christina K. Edgerly Olivia L. Bordiuk Karen Smith Samantha A. Matson Wayne R. Matson Clemens R. Scherzer H. Diana Rosas Steven M. Hersch Robert J. Ferrante 《生物化学与生物物理学报:疾病的分子基础》2010,1802(7-8):673-681
A major goal of current clinical research in Huntington's disease (HD) has been to identify preclinical and manifest disease biomarkers, as these may improve both diagnosis and the power for therapeutic trials. Although the underlying biochemical alterations and the mechanisms of neuronal degeneration remain unknown, energy metabolism defects in HD have been chronicled for many years. We report that the brain isoenzyme of creatine kinase (CK-BB), an enzyme important in buffering energy stores, was significantly reduced in presymptomatic and manifest disease in brain and blood buffy coat specimens in HD mice and HD patients. Brain CK-BB levels were significantly reduced in R6/2 mice by ~ 18% to ~ 68% from 21 to 91 days of age, while blood CK-BB levels were decreased by ~ 14% to ~ 44% during the same disease duration. Similar findings in CK-BB levels were observed in the 140 CAG mice from 4 to 12 months of age, but not at the earliest time point, 2 months of age. Consistent with the HD mice, there was a grade-dependent loss of brain CK-BB that worsened with disease severity in HD patients from ~ 28% to ~ 63%, as compared to non-diseased control patients. In addition, CK-BB blood buffy coat levels were significantly reduced in both premanifest and symptomatic HD patients by ~ 23% and ~ 39%, respectively. The correlation of CK-BB as a disease biomarker in both CNS and peripheral tissues from HD mice and HD patients may provide a powerful means to assess disease progression and to predict the potential magnitude of therapeutic benefit in this disorder. 相似文献
126.
Clemens Röhrl Tamara A. Pagler Witta Strobl Adolf Ellinger Josef Neumüller Margit Pavelka Herbert Stangl Claudia Meisslitzer-Ruppitsch 《Histochemistry and cell biology》2010,133(3):261-272
Holo-high density lipoprotein (HDL) particle uptake, besides selective lipid uptake, constitutes an alternative pathway to
regulate cellular cholesterol homeostasis. In the current study, the cellular path of holo-HDL particles was investigated
in human liver carcinoma cells (HepG2) using combined light and electron microscopical methods. The apolipoprotein moiety
of HDL was visualized with different markers: horseradish peroxidase, colloidal gold and the fluorochrome Alexa568, used in fluorescence microscopy and after photooxidation correlatively at the ultrastructural level. Time course experiments
showed a rapid uptake of holo-HDL particles, an accumulation in endosomal compartments, with a plateau after 1–2 h of continuous
uptake, and a clearance 1–2 h upon replacement by unlabeled HDL. Correlative microscopy, using HDL-Alexa568-driven diaminobenzidine (DAB) photooxidation, identified the fluorescent organelles as DAB-positive multivesicular bodies
(MVBs) in the electron microscope; their luminal contents but not the internal vesicles were stained. Labeled MVBs increased
in numbers and changed shapes along with the duration of uptake, from polymorphic organelles with multiple surface domains
and differently shaped protrusions dominating at early times of uptake to compact bodies with mainly tubular appendices and
densely packed vesicles after later times. Differently shaped and labeled surface domains and appendices, as revealed by three
dimensional reconstructions, as well as images of homotypic fusions indicate the dynamics of the HDL-positive MVBs. Double
staining visualized by confocal microscopy, along with the electron microscopic data, shows that holo-HDL particles after
temporal storage in MVBs are only to a minor degree transported to lysosomes, which suggests that different mechanisms are
involved in cellular HDL clearance, including resecretion. 相似文献
127.
Laszlo Revesz Achim Schlapbach Reiner Aichholz Janet Dawson Roland Feifel Stuart Hawtin Amanda Littlewood-Evans Guido Koch Markus Kroemer Henrik Möbitz Clemens Scheufler Juraj Velcicky Christine Huppertz 《Bioorganic & medicinal chemistry letters》2010,20(15):4719-4723
Spirocyclopropane- and spiroazetidine-substituted tetracycles 13D–E and 16A are described as orally active MK2 inhibitors. The spiroazetidine derivatives are potent MK2 inhibitors with IC50 <3 nM and inhibit the release of TNFα (IC50<0.3 μM) from hPBMCs and hsp27 phosphorylation in anisomycin stimulated THP-1 cells. The spirocyclopropane analogues are less potent against MK2 (IC50 = 0.05–0.23 μM), less potent in cells (IC50 <1.1 μM), but show good oral absorption. Compound 13E (100 mg/kg po; bid) showed oral activity in rAIA and mCIA, with significant reduction of swelling and histological score. 相似文献
128.
Hugo Alves Ursula Munoz‐Najar Jan De Wit Auke J. S. Renard Jan H. J. Hoeijmakers John M. Sedivy Clemens Van Blitterswijk Jan De Boer 《Journal of cellular and molecular medicine》2010,14(12):2729-2738
Human mesenchymal stromal cells (hMSCs) represent an attractive cell source for clinic applications. Besides being multi‐potent, recent clinical trials suggest that they secrete both trophic and immunomodulatory factors, allowing allogenic MSCs to be used in a wider variety of clinical situations. The yield of prospective isolation is however very low, making expansion a required step toward clinical applications. Unfortunately, this leads to a significant decrease in their stemness. To identify the mechanism behind loss of multi‐potency, hMSCs were expanded until replicative senescence and the concomitant molecular changes were characterized at regular intervals. We observed that, with time of culture, loss of multi‐potency was associated with both the accumulation of DNA damage and the respective activation of the DNA damage response pathway, suggesting a correlation between both phenomena. Indeed, exposing hMSCs to DNA damage agents led to a significant decrease in the differentiation potential. We also showed that hMSCs are susceptible to accumulate DNA damage upon in vitro expansion, and that although hMSCs maintained an effective nucleotide excision repair activity, there was a progressive accumulation of DNA damage. We propose a model in which DNA damage accumulation contributes to the loss of differentiation potential of hMSCs, which might not only compromise their potential for clinical applications but also contribute to the characteristics of tissue ageing. 相似文献
129.
Claudia A d'Alençon Oscar A Peña Christine Wittmann Viviana E Gallardo Rebecca A Jones Felix Loosli Urban Liebel Clemens Grabher Miguel L Allende 《BMC biology》2010,8(1):151
Background
Studies on innate immunity have benefited from the introduction of zebrafish as a model system. Transgenic fish expressing fluorescent proteins in leukocyte populations allow direct, quantitative visualization of an inflammatory response in vivo. It has been proposed that this animal model can be used for high-throughput screens aimed at the identification of novel immunomodulatory lead compounds. However, current assays require invasive manipulation of fish individually, thus preventing high-content screening. 相似文献130.
Roland Hausknecht Helmut Bayerl Roman Gula Ralph Kuehn 《The Journal of wildlife management》2010,74(8):1904-1910
ABSTRACT Noninvasive genetic monitoring of animal populations has become a widely used method in animal conservation and wildlife management due to its known advantages in sample availability of endangered or elusive species. A variety of methods have been suggested to overcome the difficulties of collecting reliable genetic data despite poor DNA quality and quantity of samples. We used quantitative real-time polymerase chain reaction (qPCR) to quantify DNA contents and preselect extracts suitable for microsatellite genotyping of noninvasive samples from 2 carnivore species, wolf (Canis lupus) and Eurasian otter (Lutra lutra). We tested 2 concentration thresholds for DNA extracts containing either 5 pg/μL or 25 pg/μL at minimum and evaluated the effect of excluding samples from genotyping falling below either of these DNA concentrations. Depending on species and threshold concentration applied, we reduced the genotyping effort by 21% to 47% and genotyping errors by 7% to 45%, yet we could still detect 82% to 99% of available genotypes. Thus, qPCR may potentially reduce genotyping effort and enhance data reliability in noninvasive genetic studies. Genetic laboratories working on noninvasive population genetic studies could transfer this approach to other species, streamline genetic analyses and, thus, more efficiently provide wildlife managers with reliable genetic data of wild populations. 相似文献