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排序方式: 共有398条查询结果,搜索用时 0 毫秒
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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
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Tomaso Patarnello Stefania Marcato Lorenzo Zane Vittorio Varotto Luca Bargelloni 《Molecular phylogenetics and evolution》2003,28(3):420
Antarctic fish of the suborder Notothenioidei represent one of the most notable examples of adaptive radiation in the marine environment. The evolutionary relationships between and within the eight families of this suborder have been well established by numerous studies, whereas the microevolutionary processes of notothenioid species remain largely unexplored. In the present paper we investigated the evolutionary relationships between three closely related species of the genus Chionodraco (family Channichthyidae), namely Chionodraco hamatus, Chionodraco rastrospinosus, and Chionodraco myersi by analysing portions of the mitochondrial genome (D-loop and 16S rRNA). The taxonomic status of C. hamatus and C. rastrospinosus as separate species has been questioned because of the limited number of key morphological characters that distinguish these two taxa. Our results, based on the analysis of several specimens belonging to both morphological groups revealed a small genetic differentiation among haplotypes, however, a clear separation between the two nominal species emerged since all individuals of each of the two taxa clustered together in distinct monophyletic groups. C. myersi appeared more distantly related in the phylogenetic analysis. For one species, C. hamatus, sampling was carried out at three different geographic locations in the area of the Ross Sea and Weddell Sea. The results showed that the partition of the genetic variation within this species is not compatible with the hypothesis of panmixia as gene flow between populations was significantly reduced. 相似文献
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Cantuti-Castelvetri I Hernandez LF Keller-McGandy CE Kett LR Landy A Hollingsworth ZR Saka E Crittenden JR Nillni EA Young AB Standaert DG Graybiel AM 《PloS one》2010,5(11):e13861
Background
Dyskinesias associated with involuntary movements and painful muscle contractions are a common and severe complication of standard levodopa (L-DOPA, L-3,4-dihydroxyphenylalanine) therapy for Parkinson''s disease. Pathologic neuroplasticity leading to hyper-responsive dopamine receptor signaling in the sensorimotor striatum is thought to underlie this currently untreatable condition.Methodology/Principal Findings
Quantitative real-time polymerase chain reaction (PCR) was employed to evaluate the molecular changes associated with L-DOPA-induced dyskinesias in Parkinson''s disease. With this technique, we determined that thyrotropin releasing hormone (TRH) was greatly increased in the dopamine-depleted striatum of hemi-parkinsonian rats that developed abnormal movements in response to L-DOPA therapy, relative to the levels measured in the contralateral non-dopamine-depleted striatum, and in the striatum of non-dyskinetic control rats. ProTRH immunostaining suggested that TRH peptide levels were almost absent in the dopamine-depleted striatum of control rats that did not develop dyskinesias, but in the dyskinetic rats, proTRH immunostaining was dramatically up-regulated in the striatum, particularly in the sensorimotor striatum. This up-regulation of TRH peptide affected striatal medium spiny neurons of both the direct and indirect pathways, as well as neurons in striosomes.Conclusions/Significance
TRH is not known to be a key striatal neuromodulator, but intrastriatal injection of TRH in experimental animals can induce abnormal movements, apparently through increasing dopamine release. Our finding of a dramatic and selective up-regulation of TRH expression in the sensorimotor striatum of dyskinetic rat models suggests a TRH-mediated regulatory mechanism that may underlie the pathologic neuroplasticity driving dopamine hyper-responsivity in Parkinson''s disease. 相似文献68.
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目的:建立人CTRP4基因的转基因小鼠,为脂肪细胞因子CTRP4的体内功能研究奠定基础。方法首先构建人CTRP4的转基因小鼠线性化表达载体,再利用显微注射的方法将载体注射入小鼠受精卵,从而构建人CTRP4的首建鼠( Founder )并与野生型小鼠交配繁殖得到F1代阳性小鼠,再通过近亲繁殖与测交的方法,得到CTRP4转基因纯合子小鼠,并通过PCR和western blot 的方法对纯合子小鼠进行鉴定。结果得到人CTRP4转基因小鼠纯合子小鼠两个品系,western blot鉴定该转基因小鼠心脏,肝脏,脑,肾脏等多种组织中均呈现CTRP4高表达。结论成功构建了人CTRP4转基因小鼠纯合子小鼠。 相似文献