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排序方式: 共有416条查询结果,搜索用时 15 毫秒
131.
132.
Laura J. Goodall Milan Ovecka Daniel Rycroft Sarah L. Friel Andrew Sanderson Prafull Mistry Marie L. Davies A. Allart Stoop 《PloS one》2015,10(9)
Tumour Necrosis Factor-α (TNF-α) inhibition has been transformational in the treatment of patients with inflammatory disease, e.g. rheumatoid arthritis. Intriguingly, TNF-α signals through two receptors, TNFR1 and TNFR2, which have been associated with detrimental inflammatory and beneficial immune-regulatory processes, respectively. To investigate if selective TNFR1 inhibition might provide benefits over pan TNF-α inhibition, tools to investigate the potential impact of pharmacological intervention are needed. Receptor-deficient mice have been very insightful, but are not reversible and could distort receptor cross-talk, while inhibitory anti-TNFR1 monoclonal antibodies have a propensity to induce receptor agonism. Therefore, we set out to characterise a monovalent anti-TNFR1 domain antibody (dAb) formatted for in vivo use. The mouse TNFR1 antagonist (DMS5540) is a genetic fusion product of an anti-TNFR1 dAb with an albumin-binding dAb (AlbudAb). It bound mouse TNFR1, but not human TNFR1, and was an antagonist of TNF-α-mediated cytotoxicity in a L929 cell assay. Surprisingly, the dAb did not compete with TNF-α for TNFR1-binding. This was supported by additional data showing the anti-TNFR1 epitope mapped to a single residue in the first domain of TNFR1. Pharmacokinetic studies of DMS5540 in mice over three doses (0.1, 1.0 and 10 mg/kg) confirmed extended in vivo half-life, mediated by the AlbudAb, and demonstrated non-linear clearance of DMS5540. Target engagement was further confirmed by dose-dependent increases in total soluble TNFR1 levels. Functional in vivo activity was demonstrated in a mouse challenge study, where DMS5540 provided dose-dependent inhibition of serum IL-6 increases in response to bolus mouse TNF-α injections. Hence, DMS5540 is a potent mouse TNFR1 antagonist with in vivo pharmacokinetic and pharmacodynamic properties compatible with use in pre-clinical disease models and could provide a useful tool to dissect the individual contributions of TNFR1 and TNFR2 in homeostasis and disease. 相似文献
133.
Daniel W. Thomson Katherine A. Pillman Matthew L. Anderson David M. Lawrence John Toubia Gregory J. Goodall Cameron P. Bracken 《Nucleic acids research》2015,43(1):470-481
High-throughput sequencing reveals an abundance of microRNA-sized fragments derived from larger non-coding RNAs. Roles for these small RNAs in gene silencing are suggested by their co-precipitation with Argonaute, the microRNA effector protein, though the extent to which they suppress gene expression endogenously remains unclear. To address this, we used luciferase reporters to determine the endogenous functionality of small RNAs from a diverse range of sources. We demonstrate small RNAs derived from snoRNAs have the capacity to act in a microRNA-like manner, though we note the vast majority of these are bound to Argonaute at levels below that required for detectable silencing activity. We show Argonaute exhibits a high degree of selectivity for the small RNAs with which it interacts and note that measuring Argonaute-associated levels is a better indicator of function than measuring total expression. Although binding to Argonaute at sufficient levels is necessary for demonstrating microRNA functionality in our reporter assay, this alone is not enough as some small RNAs derived from other non-coding RNAs (tRNAs, rRNAs, Y-RNAs) are associated with Argonaute at very high levels yet do not serve microRNA-like roles. 相似文献
134.
Allelic expression mapping across cellular lineages to establish impact of non‐coding SNPs 下载免费PDF全文
135.
Loukia G Tsaprouni Tsun-Po Yang Jordana Bell Katherine J Dick Stavroula Kanoni James Nisbet Ana Vi?uela Elin Grundberg Christopher P Nelson Eshwar Meduri Alfonso Buil Francois Cambien Christian Hengstenberg Jeanette Erdmann Heribert Schunkert Alison H Goodall Willem H Ouwehand Emmanouil Dermitzakis Tim D Spector Nilesh J Samani Panos Deloukas 《Epigenetics》2014,9(10):1382-1396
Smoking is a major risk factor in many diseases. Genome wide association studies have linked genes for nicotine dependence and smoking behavior to increased risk of cardiovascular, pulmonary, and malignant diseases. We conducted an epigenome wide association study in peripheral-blood DNA in 464 individuals (22 current smokers and 263 ex-smokers), using the Human Methylation 450 K array. Upon replication in an independent sample of 356 twins (41 current and 104 ex-smokers), we identified 30 probes in 15 distinct loci, all of which reached genome-wide significance in the combined analysis P < 5 × 10−8. All but one probe (cg17024919) remained significant after adjusting for blood cell counts. We replicated all 9 known loci and found an independent signal at CPOX near GPR15. In addition, we found 6 new loci at PRSS23, AVPR1B, PSEN2, LINC00299, RPS6KA2, and KIAA0087. Most of the lead probes (13 out of 15) associated with cigarette smoking, overlapped regions of open chromatin (FAIRE and DNaseI hypersensitive sites) or / and H3K27Ac peaks (ENCODE data set), which mark regulatory elements. The effect of smoking on DNA methylation was partially reversible upon smoking cessation for longer than 3 months. We report the first statistically significant interaction between a SNP (rs2697768) and cigarette smoking on DNA methylation (cg03329539). We provide evidence that the metSNP for cg03329539 regulates expression of the CHRND gene located circa 95 Kb downstream of the methylation site. Our findings suggest the existence of dynamic, reversible site-specific methylation changes in response to cigarette smoking , which may contribute to the extended health risks associated with cigarette smoking. 相似文献
136.
D. W. Goodall 《Plant biosystems》2013,147(6):1346-1354
Using a data base underpinned by probability considerations in which a variety of attributes, some of which may be quantitative, are recorded for a number of “operational taxonomic units” (OTUs), a key system is described by which an unnamed specimen may quickly be identified. The concept of “diagnostic power” is introduced, by which each attribute is evaluated in terms of its potential contribution to identifying the unnamed specimen. Besides coverage of different types of attributes and the introduction of “diagnostic power”, the system has the advantages of incorporating multiple values of an attribute for each OTU and offering short-cuts to identification. 相似文献
137.
Ana Lonic Freya Gehling Leila Belle Xiaochun Li Nicole L. Schieber Elizabeth V. Nguyen Gregory J. Goodall Robert G. Parton Roger J. Daly Yeesim Khew-Goodall 《The Journal of cell biology》2021,220(2)
Receptor degradation terminates signaling by activated receptor tyrosine kinases. Degradation of EGFR occurs in lysosomes and requires the switching of RAB5 for RAB7 on late endosomes to enable their fusion with the lysosome, but what controls this critical switching is poorly understood. We show that the tyrosine kinase FER alters PKCδ function by phosphorylating it on Y374, and that phospho-Y374-PKCδ prevents RAB5 release from nascent late endosomes, thereby inhibiting EGFR degradation and promoting the recycling of endosomal EGFR to the cell surface. The rapid association of phospho-Y374-PKCδ with EGFR-containing endosomes is diminished by PTPN14, which dephosphorylates phospho-Y374-PKCδ. In triple-negative breast cancer cells, the FER-dependent phosphorylation of PKCδ enhances EGFR signaling and promotes anchorage-independent cell growth. Importantly, increased Y374-PKCδ phosphorylation correlating with arrested late endosome maturation was identified in ∼25% of triple-negative breast cancer patients, suggesting that dysregulation of this pathway may contribute to their pathology. 相似文献
138.
An autocrine TGF-beta/ZEB/miR-200 signaling network regulates establishment and maintenance of epithelial-mesenchymal transition 总被引:1,自引:0,他引:1
139.
Jeremy Goodall Ed T. F. Witkowski Craig D. Morris Lesley Henderson 《Biological invasions》2011,13(10):2217-2231
The absence of natural enemies being keystone to the success of invasive alien plants (IAPs) can only be accepted once all
the factors governing the invader and the ecosystems it invades have been established. Few studies have attempted this approach.
This study reports on the relations between the invasive alien forb Campuloclinium macrocephalum (Less.) DC. (pompom weed), herbivory and the ecology of the rangelands invaded in South Africa. Eighty invaded rangelands
in Gauteng Province were studied. Pompom weed herbivory was insignificant with the greatest damage being caused by native
grasshoppers. Rainfall, topography and soil texture were the primary drivers of vegetation pattern. Pompom weed exhibited
disturbance-mediated invasion strategies, favouring rangelands affected by non-sustainable commercial grazing practices, abandoned
agricultural fields and drained wetlands. It invaded vegetation in poor condition with sward basal cover <19%. Weed density
was exacerbated by high fire frequency. Vegetation susceptible to pompom weed was also invaded by other alien and native pasture
weeds. The absence of natural enemies could give pompom weed a competitive advantage over native pioneer cohorts in disturbed
rangelands, but is unlikely to increase fitness enabling its establishment in vegetation in good condition. Grazing strategies
that promote the dominance of grass species adapted to frequent non-selective defoliation appear to restrict pompom weed better
than degraded rangelands that are not utilised. Biotic resistance of rangelands to pompom weed invasion will be greatest in
vegetation in good condition and under good management. The low abundance of pompom weed in rangelands in communal areas and
fence-line contrasts in invaded and un-invaded road reserves warrants further investigation. 相似文献
140.
Maritza Sepúlveda Doris Oliva L. René Duran Alejandra Urra Susana N. Pedraza Patrícia Majluf Natalie Goodall Enrique A. Crespo 《Oecologia》2013,171(4):809-817
We tested the validity of Bergmann’s rule and Rosenzweig’s hypothesis through an analysis of the geographical variation of the skull size of Otaria flavescens along the entire distribution range of the species (except Brazil). We quantified the sizes of 606 adult South American sea lion skulls measured in seven localities of Peru, Chile, Uruguay, Argentina, and the Falkland/Malvinas Islands. Geographical and environmental variables included latitude, longitude, and monthly minimum, maximum, and mean air and ocean temperatures. We also included information on fish landings as a proxy for productivity. Males showed a positive relationship between condylobasal length (CBL) and latitude, and between CBL and the six temperature variables. By contrast, females showed a negative relationship between CBL and the same variables. Finally, female skull size showed a significant and positive correlation with fish landings, while males did not show any relationship with this variable. The body size of males conformed to Bergmann’s rule, with larger individuals found in southern localities of South America. Females followed the converse of Bergmann’s rule at the intraspecific level, but showed a positive relationship with the proxy for productivity, thus supporting Rosenzweig’s hypothesis. Differences in the factors that drive body size in females and males may be explained by their different life-history strategies. Our analyses demonstrate that latitude and temperature are not the only factors that explain spatial variation in body size: others such as food availability are also important for explaining the ecogeographical patterns found in O. flavescens. 相似文献