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91.
H Diehl J Sch?delin V Ullrich 《Hoppe-Seyler's Zeitschrift für physiologische Chemie》1970,351(11):1359-1371
92.
93.
J. Nathaniel Diehl Jennifer E. Klomp Kayla R. Snare Priya S. Hibshman Devon R. Blake Zane D. Kaiser Thomas S.K. Gilbert Elisa Baldelli Mariaelena Pierobon Bjrn Papke Runying Yang Richard G. Hodge Naim U. Rashid Emanuel F. Petricoin III Laura E. Herring Lee M. Graves Adrienne D. Cox Channing J. Der 《The Journal of biological chemistry》2021,297(5)
Oncogenic KRAS drives cancer growth by activating diverse signaling networks, not all of which have been fully delineated. We set out to establish a system-wide profile of the KRAS-regulated kinase signaling network (kinome) in KRAS-mutant pancreatic ductal adenocarcinoma (PDAC). We knocked down KRAS expression in a panel of six cell lines and then applied multiplexed inhibitor bead/MS to monitor changes in kinase activity and/or expression. We hypothesized that depletion of KRAS would result in downregulation of kinases required for KRAS-mediated transformation and in upregulation of other kinases that could potentially compensate for the deleterious consequences of the loss of KRAS. We identified 15 upregulated and 13 downregulated kinases in common across the panel of cell lines. In agreement with our hypothesis, all 15 of the upregulated kinases have established roles as cancer drivers (e.g., SRC, TGF-β1, ILK), and pharmacological inhibition of one of these upregulated kinases, DDR1, suppressed PDAC growth. Interestingly, 11 of the 13 downregulated kinases have established driver roles in cell cycle progression, particularly in mitosis (e.g., WEE1, Aurora A, PLK1). Consistent with a crucial role for the downregulated kinases in promoting KRAS-driven proliferation, we found that pharmacological inhibition of WEE1 also suppressed PDAC growth. The unexpected paradoxical activation of ERK upon WEE1 inhibition led us to inhibit both WEE1 and ERK concurrently, which caused further potent growth suppression and enhanced apoptotic death compared with WEE1 inhibition alone. We conclude that system-wide delineation of the KRAS-regulated kinome can identify potential therapeutic targets for KRAS-mutant pancreatic cancer. 相似文献
94.
Grard Donz Silvia Schnyder-Candrian Stefan Bogdanov Peter-Allan Diehl Patrick M. Guerin Verena Kilchenman Florian Monachon 《Archives of insect biochemistry and physiology》1998,37(2):129-145
The ectoparasitic mite Varroa jacobsoni reproduces in the capped brood of the honey bees Apis cerana and Apis mellifera. Observations on the reproductive behavior of the mite have shown a well-structured spatial allocation of its activity using the bee or cell wall for different behaviors. The resulting advantages for the parasite of this subdivision of the concealed brood environment suggests an important role for chemostimuli in these substrates. Extracts of the European honey bee cocoons induce a strong arrestment response in the mite, as indicated by prolonged periods of walking on the extracts applied on a semipermeable membrane and by systematically returning to the stimulus after encountering the treatment borders. Two thin-layer chromatography fractions of the cocoon extract eliciting arrestment were found to contain saturated C17 to C22 primary aliphatic alcohols and C19 to C22 aldehydes. We analyzed extracts of the cocoon and different larvae, pupae, and adults of both worker and drone A. mellifera to determine the relative amounts of these chemostimuli in the different substrates employed by Varroa. Both aldehydes and alcohols were more abundant in the cocoon than in the cuticle of adult or developing bees. Mixtures of the aliphatic alcohols and aldehydes at the proportions found in the cocoons acted synergistically on the arrestment response, but this activity disappeared when mixed in equal amounts. When these oxygenated chemostimuli were mixed with C19 to C25 alkanes at the proportions found in the cocoon extract, we observed a significantly lower threshold for the chemostimulant mixture. These results indicate how Varroa may use mixtures of rarer products to differentiate between substrates and host stages during its developmental cycle within honey bee brood cells. Arch. Insect Biochem. Physiol. 37:129–145, 1998. © 1998 Wiley-Liss, Inc. 相似文献
95.
Annika Wagner Erika Diehl R. Luise Krauth-Siegel Ute A. Hellmich 《Biomolecular NMR assignments》2017,11(2):193-196
Tryparedoxin (Tpx) is a pivotal protein in the redox-metabolism of trypanosomatid parasites. Tpx has previously been identified as a potential target for drug development in the fight against human African sleeping sickness caused by Trypanosoma brucei. Tpx belongs to the thioredoxin superfamily and acts as an oxidoreductase in the parasite’s cytoplasm. It contains a WCPPC active site motif, which enables the protein to undergo thiol-disulfide exchange. To promote future protein-drug interaction analyses, we report the 1H, 13C and 15N backbone chemical shift assignments for both the oxidized and reduced states of Tpx. The redox state of the protein has a significant impact on the chemical shifts of the residues at the active site of the protein, especially on the two redox active site cysteines. The NMR assignments presented here will be a prerequisite for investigating drug binding to Tpx in molecular detail and to drive further drug optimization. 相似文献
96.
Diehl F Schmidt K Choti MA Romans K Goodman S Li M Thornton K Agrawal N Sokoll L Szabo SA Kinzler KW Vogelstein B Diaz LA 《Nature medicine》2008,14(9):985-990
The measurement of circulating nucleic acids has transformed the management of chronic viral infections such as HIV. The development of analogous markers for individuals with cancer could similarly enhance the management of their disease. DNA containing somatic mutations is highly tumor specific and thus, in theory, can provide optimum markers. However, the number of circulating mutant gene fragments is small compared to the number of normal circulating DNA fragments, making it difficult to detect and quantify them with the sensitivity required for meaningful clinical use. In this study, we applied a highly sensitive approach to quantify circulating tumor DNA (ctDNA) in 162 plasma samples from 18 subjects undergoing multimodality therapy for colorectal cancer. We found that ctDNA measurements could be used to reliably monitor tumor dynamics in subjects with cancer who were undergoing surgery or chemotherapy. We suggest that this personalized genetic approach could be generally applied to individuals with other types of cancer. 相似文献
97.
Cristie Grazziotin Noschang Rachel Krolow Leticia Ferreira Pettenuzzo Mônica Colpini Ávila Andrelisa Fachin Danusa Arcego Eduardo von Pozzer Toigo Leonardo Machado Crema Luísa Amália Diehl Deusa Vendite Carla Dalmaz 《Neurochemical research》2009,34(9):1568-1574
We studied the effect of chronic caffeine on parameters related to oxidative stress in different brain regions of stressed
and non-stressed rats. Wistar rats were divided into three groups: control (receiving water), caffeine 0.3 g/L and caffeine
1.0 g/L (in the drinking water). These groups were subdivided into non-stressed and stressed (repeated restraint stress during
40 days). Lipid peroxide levels and the total radical-trapping potential were assessed, as well as antioxidant enzyme activities
superoxide dismutase, gluthatione peroxidase, and catalase in hippocampus, striatum and cerebral cortex. Results showed interactions
between stress and caffeine, especially in the cerebral cortex, since caffeine increased the activity of some antioxidant
enzymes, but not in stressed animals. We concluded that chronic administration of caffeine led, in some cases, to increased
activity of antioxidant enzymes. However, these effects were not observed in the stressed animals. 相似文献
98.
Primates have long been a favorite subject of evolutionary biologists, and in recent decades, have come to play an increasingly important role in biomedical research, including comparative genetics and phylogenetics. The growing list of annotated genome databases from nonhuman primate species is expected to aid in these endeavors, allowing many analyses to be performed partially or even entirely in silico. However, whole genome sequence data are typically derived from only one, or at best a few, individuals. As a consequence, information in the databases does not capture variation within species or populations, nor can the sequence of one individual be taken as representative across all loci. Furthermore, the vast majority of primate species have not been sequenced, and only a small percentage of species are currently slated for whole genome sequencing efforts. Finally, for many species data on patterns and levels of RNA expression will be lacking. Thus, there will continue to be a demand for samples from nonhuman primates as raw material for genetic and phylogenetic analyses. Gathering such samples can be complicated, with many legal and practical barriers to obtaining samples in the field or transporting samples between research centers and across borders. Here, we provide basic but critical advice for those initiating studies requiring genetic material from nonhuman primates, including some guidance on how to locate and obtain samples, brief overviews of common protocols for handling and processing samples, and a table of useful links for locating resources related to the acquisition of samples. We also advocate for the creation of curated banks of nonhuman primate samples, particularly renewable sources of genetic material such as immortalized cell lines or fibroblasts, to reduce the need for repeated or redundant sampling from living animals. 相似文献
99.
Salmon D do Aido-Machado R Diehl A Leidert M Schmetzer O de A Lima AP Scharfstein J Oschkinat H Pires JR 《Journal of molecular biology》2006,357(5):1511-1521
A Trypanosoma cruzi cysteine protease inhibitor, termed chagasin, is the first characterized member of a new family of tight-binding cysteine protease inhibitors identified in several lower eukaryotes and prokaryotes but not present in mammals. In the protozoan parasite T.cruzi, chagasin plays a role in parasite differentiation and in mammalian host cell invasion, due to its ability to modulate the endogenous activity of cruzipain, a lysosomal-like cysteine protease. In the present work, we determined the solution structure of chagasin and studied its backbone dynamics by NMR techniques. Structured as a single immunoglobulin-like domain in solution, chagasin exerts its inhibitory activity on cruzipain through conserved residues placed in three loops in the same side of the structure. One of these three loops, L4, predicted to be of variable length among chagasin homologues, is flexible in solution as determined by measurements of (15)N relaxation. The biological implications of structural homology between chagasin and other members of the immunoglobulin super-family are discussed. 相似文献
100.