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21.
Vaccination with a Melan-A peptide selects an oligoclonal T cell population with increased functional avidity and tumor reactivity 总被引:4,自引:0,他引:4
Valmori D Dutoit V Schnuriger V Quiquerez AL Pittet MJ Guillaume P Rubio-Godoy V Walker PR Rimoldi D Liénard D Cerottini JC Romero P Dietrich PY 《Journal of immunology (Baltimore, Md. : 1950)》2002,168(8):4231-4240
Both the underlying molecular mechanisms and the kinetics of TCR repertoire selection following vaccination against tumor Ags in humans have remained largely unexplored. To gain insight into these questions, we performed a functional and structural longitudinal analysis of the TCR of circulating CD8(+) T cells specific for the HLA-A2-restricted immunodominant epitope from the melanocyte differentiation Ag Melan-A in a melanoma patient who developed a vigorous and sustained Ag-specific T cell response following vaccination with the corresponding synthetic peptide. We observed an increase in functional avidity of Ag recognition and in tumor reactivity in the postimmune Melan-A-specific populations as compared with the preimmune blood sample. Improved Ag recognition correlated with an increase in the t(1/2) of peptide/MHC interaction with the TCR as assessed by kinetic analysis of A2/Melan-A peptide multimer staining decay. Ex vivo analysis of the clonal composition of Melan-A-specific CD8(+) T cells at different time points during vaccination revealed that the response was the result of asynchronous expansion of several distinct T cell clones. Some of these T cell clones were also identified at a metastatic tumor site. Collectively, these data show that tumor peptide-driven immune stimulation leads to the selection of high-avidity T cell clones of increased tumor reactivity that independently evolve within oligoclonal populations. 相似文献
22.
Background
T7 based linear amplification of RNA is used to obtain sufficient antisense RNA for microarray expression profiling. We optimized and systematically evaluated the fidelity and reproducibility of different amplification protocols using total RNA obtained from primary human breast carcinomas and high-density cDNA microarrays. 相似文献23.
24.
Uncoupling protein 2: a novel player in neuroprotection 总被引:4,自引:0,他引:4
Paradis E Clavel S Bouillaud F Ricquier D Richard D 《Trends in molecular medicine》2003,9(12):522-525
A recent report provides exciting new evidence that suggests that uncoupling protein 2 (UCP2), a mitochondrial protein expressed in specific cells of numerous tissues, might be neuroprotective by reducing mitochondrial Ca2+ uptake and preventing mitochondrial accumulation of reactive oxygen species (ROS) following cerebral ischemia. The mitochondrial sequestration of Ca2+ and ROS, which depends on the mitochondrial membrane potential (ΔΨm), is a deleterious consequence of excitotoxicity. A neuroprotective role for Ucp2 is consistent with the already proposed property of this gene in mitigating cellular damage caused by ROS. 相似文献
25.
26.
EMMANUEL Paradis 《Evolutionary ecology》1998,12(2):235-244
The evolution of dispersal rate is studied with a model of several local populations linked by dispersal. Three dispersal
strategies are considered where all, half or none of the offspring disperse. The spatial scale (number of patches) and the
temporal scale (probability of local extinction) of the environment are critical in determining the selective advantage of
the different dispersal strategies. The results from the simulations suggest that an interaction between group selection and
individual selection results in a different outcome in relation to the spatial and temporal scales of the environment. Such
an interaction is able to maintain a polymorphism in dispersal strategies. The maintenance of this polymorphism is also scale-dependent.
This study suggests a mechanism for the short-term evolution of dispersal, and provides a testable prediction of this hypothesis,
namely that loss of dispersal abilities should be more frequent in spatially more continuous environments, or in temporally
more stable environments.
This revised version was published online in July 2006 with corrections to the Cover Date. 相似文献
27.
Kaja S. Borge Silje Nord Peter Van Loo Ole C. Lingj?rde Gjermund Gunnes Grethe I. G. Aln?s Hiroko K. Solvang Torben Lüders Vessela N. Kristensen Anne-Lise B?rresen-Dale Frode Lingaas 《PloS one》2015,10(5)
BackgroundCopy number aberrations frequently occur during the development of many cancers. Such events affect dosage of involved genes and may cause further genomic instability and progression of cancer. In this survey, canine SNP microarrays were used to study 117 canine mammary tumours from 69 dogs.ResultsWe found a high occurrence of copy number aberrations in canine mammary tumours, losses being more frequent than gains. Increased frequency of aberrations and loss of heterozygosity were positively correlated with increased malignancy in terms of histopathological diagnosis. One of the most highly recurrently amplified regions harbored the MYC gene. PTEN was located to a frequently lost region and also homozygously deleted in five tumours. Thus, deregulation of these genes due to copy number aberrations appears to be an important event in canine mammary tumour development. Other potential contributors to canine mammary tumour pathogenesis are COL9A3, INPP5A, CYP2E1 and RB1. The present study also shows that a more detailed analysis of chromosomal aberrations associated with histopathological parameters may aid in identifying specific genes associated with canine mammary tumour progression.ConclusionsThe high frequency of copy number aberrations is a prominent feature of canine mammary tumours as seen in other canine and human cancers. Our findings share several features with corresponding studies in human breast tumours and strengthen the dog as a suitable model organism for this disease. 相似文献
28.
Florent Guérin Mathilde Wagner Antoine Liné Magaly Zappa Magali Fasseu Valérie Paradis Valérie Vilgrain Bernard E. Van Beers Josette Legagneux Richard Moreau Philippe Lettéron 《PloS one》2015,10(5)
MethodsWe conducted an experimental study comparing portacaval shunt (PCS), total portal vein ligation (PVL), and sham (S) operated rats. Each group were either sacrificed at 6 weeks (early) or 6 months (late). Arterial liver perfusion was studied in vivo using CT, and histopathological changes were noted. Liver mRNA levels were quantified by RT-QPCR for markers of inflammation (Il10, Tnfa), proliferation (Il6st, Mki67, Hgf, Hnf4a), angiogenesis: (Vegfa, Vegfr 1, 2 and 3; Pgf), oxidative stress (Nos2, and 3, Hif1a), and fibrosis (Tgfb). PCS and PVL were compared to the S group.ResultsPeriportal fibrosis and arterial proliferation was observed in late PCS and PVL groups. CT imaging demonstrated increased arterial liver perfusion in the PCS group. RT-QPCR showed increased inflammatory markers in PCS and PVL early groups. Tnfa and Il10 were increased in PCS and PVL late groups respectively. All proliferative markers increased in the PCS, and Hnf4a in the PVL early groups. Mki67 and Hnf4a were increased in the PCS late group. Nos3 was increased in the early and late PCS groups, and Hif1a was decreased in the PVL groups. Markers of angiogenesis were all increased in the early PCS group, and Vegfr3 and Pgf in the late PCS group. Only Vegfr3 was increased in the PVL groups. Tgf was increased in the PCS groups.ConclusionsPortal deprivation in rats induces a sustained increase in intrahepatic markers of inflammation, angiogenesis, proliferation, and fibrosis. 相似文献
29.
Laxmi Silwal-Pandit Hege Russnes Elin Borgen Veronica Skarpeteig Hans Kristian Moen Vollan Ellen Schlichting Rolf K?resen Bj?rn Naume Anne-Lise B?rresen-Dale Marianne Farnebo Anita Langer?d 《PloS one》2015,10(10)
WRAP53 protein controls intracellular trafficking of DNA repair proteins, the telomerase enzyme, and splicing factors. Functional loss of the protein has been linked to carcinogenesis, premature aging and neurodegeneration. The aim of this study was to investigate the prognostic significance of WRAP53 protein expression in breast cancer. A tissue microarray was constructed from primary breast tumors and immunostained by a polyclonal WRAP53 antibody to assess the protein expression pattern. Two different patient cohorts with long term follow-up were studied; a test- and a validation set of 154 and 668 breast tumor samples respectively. Breast cancer patients with tumor cells lacking the expression of WRAP53 in the nucleus had a significantly poorer outcome compared to patients with tumor cells expressing this protein in the nuclei (HR = 1.95, 95%CI = 1.09–3.51, p = 0.025). Nuclear localization of WRAP53 was further shown to be an independent marker of prognosis in multivariate analysis (HR = 2.57, 95%CI = 1.27–5.19, p = 0.008), and also significantly associated with better outcome in patients with TP53 mutation. Here we show that the sub-cellular localization of the WRAP53 protein has a significant impact on breast cancer survival, and thus has a potential as a clinical marker in diagnostics and treatment. 相似文献
30.
Andreas Lerchner Rainer Machauer Claudia Betschart Siem Veenstra Heinrich Rueeger Clive McCarthy Marina Tintelnot-Blomley Anne-Lise Jaton Sabine Rabe Sandrine Desrayaud Albert Enz Matthias Staufenbiel Paolo Paganetti Jean-Michel Rondeau Ulf Neumann 《Bioorganic & medicinal chemistry letters》2010,20(2):603-607
A series of macrocyclic peptidic BACE-1 inhibitors was designed. While potency on BACE-1 was rather high, the first set of compounds showed poor brain permeation and high efflux in the MDRI–MDCK assay. The replacement of the secondary benzylamino group with a phenylcyclopropylamino group maintained potency on BACE-1, while P-glycoprotein-mediated efflux was significantly reduced and brain permeation improved. Several compounds from this series demonstrated acute reduction of Aβ in human APP-wildtype transgenic (APP51/16) mice after oral administration. 相似文献