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841.
Mehmet Karaca Yuanbo Liu Zhentao Zhang Dinuka De Silva Joel S. Parker H. Shelton Earp Young E. Whang 《PloS one》2015,10(5)
Reactivation of androgen receptor (AR) may drive recurrent prostate cancer in castrate patients. Ack1 tyrosine kinase is overexpressed in prostate cancer and promotes castrate resistant xenograft tumor growth and enhances androgen target gene expression and AR recruitment to enhancers. Ack1 phosphorylates AR at Tyr-267 and possibly Tyr-363, both in the N-terminal transactivation domain. In this study, the role of these phosphorylation sites was investigated by characterizing the phosphorylation site mutants in the context of full length and truncated AR lacking the ligand-binding domain. Y267F and Y363F mutants showed decreased transactivation of reporters. Expression of wild type full length and truncated AR in LNCaP cells increased cell proliferation in androgen-depleted conditions and increased colony formation. However, the Y267F mutant of full length and truncated AR was defective in stimulating cell proliferation. The Y363F mutant was less severely affected than the Y267F mutant. The full length AR Y267F mutant was defective in nuclear translocation induced by androgen or Ack1 kinase. The truncated AR was constitutively localized to the nucleus. Chromatin immunoprecipitation analysis showed that it was recruited to the target enhancers without androgen. The truncated Y267F AR mutant did not exhibit constitutive nuclear localization and androgen enhancer binding activity. These results support the concept that phosphorylation of Tyr-267, and to a lesser extent Tyr-363, is required for AR nuclear translocation and recruitment and DNA binding and provide a rationale for development of novel approaches to inhibit AR activity. 相似文献
842.
843.
Andreas W. Schoenenberger Dennis Pfaff Boris Dasen Agne Frismantiene Paul Erne Therese J. Resink Maria Philippova 《PloS one》2015,10(6)
Close relationships exist between presence of adiponectin (APN) within vascular tissue and expression of T-cadherin (T-cad) on vascular cells. APN and T-cad are also present in the circulation but here their relationships are unknown. This study investigates associations between circulating levels of high molecular weight APN (HMW-APN) and T-cad in a population comprising 66 women and 181 men with angiographically proven stable coronary artery disease (CAD). Plasma HMW-APN and T-cad were measured by ELISA and analysed for associations with baseline clinical characteristics and with each other. In multivariable analysis BMI and HDL were independently associated with HMW-APN in both genders, while diabetes and extent of coronary stenosis were independently associated with T-cad in males only. Regression analysis showed no significant association between HMW-APN and T-cad in the overall study population. However, there was a negative association between HMW-APN and T-cad (P=0.037) in a subgroup of young men (age <60 years, had no diabetes and no or 1-vessel CAD) which persisted after multivariable analysis with adjustment for all potentially influential variables (P=0.021). In the corresponding subgroup of women there was a positive association between HMW-APN and T-cad (P=0.013) which disappeared after adjustment for HDL. After exclusion of the young men, a positive association (P=0.008) between HMW-APN and T-cad was found for the remaining participants of the overall population which disappeared after adjustment for HDL and BMI. The existence of opposing correlations between circulating HMW-APN and T-cad in male and female patient populations underscores the necessity to consider gender as a confounding variable when evaluating biomarker potentials of APN and T-cad. 相似文献
844.
Xiaobei Zhao Anyou Wang Vonn Walter Nirali M. Patel David A. Eberhard Michele C. Hayward Ashley H. Salazar Heejoon Jo Matthew G. Soloway Matthew D. Wilkerson Joel S. Parker Xiaoying Yin Guosheng Zhang Marni B. Siegel Gary B. Rosson H. Shelton Earp III Norman E. Sharpless Margaret L. Gulley Karen E. Weck D. Neil Hayes Stergios J. Moschos 《PloS one》2015,10(6)
The recent FDA approval of the MiSeqDx platform provides a unique opportunity to develop targeted next generation sequencing (NGS) panels for human disease, including cancer. We have developed a scalable, targeted panel-based assay termed UNCseq, which involves a NGS panel of over 200 cancer-associated genes and a standardized downstream bioinformatics pipeline for detection of single nucleotide variations (SNV) as well as small insertions and deletions (indel). In addition, we developed a novel algorithm, NGScopy, designed for samples with sparse sequencing coverage to detect large-scale copy number variations (CNV), similar to human SNP Array 6.0 as well as small-scale intragenic CNV. Overall, we applied this assay to 100 snap-frozen lung cancer specimens lacking same-patient germline DNA (07–0120 tissue cohort) and validated our results against Sanger sequencing, SNP Array, and our recently published integrated DNA-seq/RNA-seq assay, UNCqeR, where RNA-seq of same-patient tumor specimens confirmed SNV detected by DNA-seq, if RNA-seq coverage depth was adequate. In addition, we applied the UNCseq assay on an independent lung cancer tumor tissue collection with available same-patient germline DNA (11–1115 tissue cohort) and confirmed mutations using assays performed in a CLIA-certified laboratory. We conclude that UNCseq can identify SNV, indel, and CNV in tumor specimens lacking germline DNA in a cost-efficient fashion. 相似文献
845.
R. Mootanah J. K. Dowell K. Cheah P. Ingle J. C. Shelton 《Computer methods in biomechanics and biomedical engineering》2013,16(6):439-445
Our survey of current practice among UK orthopaedic surgeons shows wide variations in fixation techniques. The aim of this study, is to investigate the effect of drilling different configurations of anchorage holes in the acetabulum on implant stability. To avoid variables that could incur during in vitro testing, we used commercially available COSMOS finite element analysis package to investigate the stress distributions, deformations, and strains on the cement mantle when drilling three large anchorage holes and six smaller ones, with straight and rounded cement pegs. The results, which are in line with our in vitro studies on simulated reconstructed acetabulae, indicate better stability of the acetabular component when three larger holes than six smaller holes are drilled and when the necks of the anchorage holes are rounded. The longevity of total hip replacements could be improved by drilling three large anchorage holes, rather than many smaller ones, as initially proposed by Charnley. 相似文献
846.
847.
Jason Riggio Jonathan E. M. Baillie Steven Brumby Erle Ellis Christina M. Kennedy James R. Oakleaf Alex Tait Therese Tepe David M. Theobald Oscar Venter James E. M. Watson Andrew P. Jacobson 《Global Change Biology》2020,26(8):4344-4356
Leading up to the Convention on Biological Diversity Conference of the Parties 15, there is momentum around setting bold conservation targets. Yet, it remains unclear how much of Earth's land area remains without significant human influence and where this land is located. We compare four recent global maps of human influences across Earth's land, Anthromes, Global Human Modification, Human Footprint and Low Impact Areas, to answer these questions. Despite using various methodologies and data, these different spatial assessments independently estimate similar percentages of the Earth's terrestrial surface as having very low (20%–34%) and low (48%–56%) human influence. Three out of four spatial assessments agree on 46% of the non‐permanent ice‐ or snow‐covered land as having low human influence. However, much of the very low and low influence portions of the planet are comprised of cold (e.g., boreal forests, montane grasslands and tundra) or arid (e.g., deserts) landscapes. Only four biomes (boreal forests, deserts, temperate coniferous forests and tundra) have a majority of datasets agreeing that at least half of their area has very low human influence. More concerning, <1% of temperate grasslands, tropical coniferous forests and tropical dry forests have very low human influence across most datasets, and tropical grasslands, mangroves and montane grasslands also have <1% of land identified as very low influence across all datasets. These findings suggest that about half of Earth's terrestrial surface has relatively low human influence and offers opportunities for proactive conservation actions to retain the last intact ecosystems on the planet. However, though the relative abundance of ecosystem areas with low human influence varies widely by biome, conserving these last intact areas should be a high priority before they are completely lost. 相似文献
848.
Sinan Guloksuz Lotta‐Katrin Pries Margreet ten Have Ron de Graaf Saskia van Dorsselaer Boris Klingenberg Maarten Bak Bochao D. Lin Kristel R. van Eijk Philippe Delespaul Therese van Amelsvoort Jurjen J. Luykx Bart P.F. Rutten Jim van Os 《World psychiatry》2020,19(2):199-205
The validity and clinical utility of the concept of “clinical high risk” (CHR) for psychosis have so far been investigated only in risk‐enriched samples in clinical settings. In this population‐based prospective study, we aimed – for the first time – to assess the incidence rate of clinical psychosis and estimate the population attributable fraction (PAF) of that incidence for preceding psychosis risk states and DSM‐IV diagnoses of non‐psychotic mental disorders (mood disorders, anxiety disorders, alcohol use disorders, and drug use disorders). All analyses were adjusted for age, gender and education. The incidence rate of clinical psychosis was 63.0 per 100,000 person‐years. The mutually‐adjusted Cox proportional hazards model indicated that preceding diagnoses of mood disorders (hazard ratio, HR=10.67, 95% CI: 3.12‐36.49), psychosis high‐risk state (HR=7.86, 95% CI: 2.76‐22.42) and drug use disorders (HR=5.33, 95% CI: 1.61‐17.64) were associated with an increased risk for clinical psychosis incidence. Of the clinical psychosis incidence in the population, 85.5% (95% CI: 64.6‐94.1) was attributable to prior psychopathology, with mood disorders (PAF=66.2, 95% CI: 33.4‐82.9), psychosis high‐risk state (PAF=36.9, 95% CI: 11.3‐55.1), and drug use disorders (PAF=18.7, 95% CI: –0.9 to 34.6) as the most important factors. Although the psychosis high‐risk state displayed a high relative risk for clinical psychosis outcome even after adjusting for other psychopathology, the PAF was comparatively low, given the low prevalence of psychosis high‐risk states in the population. These findings provide empirical evidence for the “prevention paradox” of targeted CHR early intervention. A comprehensive prevention strategy with a focus on broader psychopathology may be more effective than the current psychosis‐focused approach for achieving population‐based improvements in prevention of psychotic disorders. 相似文献
849.
Hervé Técher Stéphane Koundrioukoff Dana Azar Therese Wilhelm Sandra Carignon Olivier Brison Michelle Debatisse Benoît Le Tallec 《Journal of molecular biology》2013
The factors that govern replication programs are still poorly identified in metazoans, especially in mammalian cells. Thanks to molecular combing, the dynamics of DNA replication can be assessed at the genome-scale level from the cumulative analysis of single DNA fibers. This technique notably enables measurement of replication fork speed and fork asymmetry and that of distances separating either initiation or termination events. The results presented here aim to evaluate requirements critical to accurate measurement of replication parameters by molecular combing. We show that sample size, fiber length and DNA counterstaining are crucial to gain robust information concerning replication dynamics. Our results thus provide a methodological frame to investigate the DNA replication program through molecular combing analyses. 相似文献
850.
Katja Ota Adrijana Leonardi Miha Mikelj Matej Skočaj Therese Wohlschlager Markus Künzler Markus Aebi Mojca Narat Igor Križaj Gregor Anderluh Kristina Sepčić Peter Maček 《Biochimie》2013
The mushroom Pleurotus ostreatus has been reported to produce the hemolytic proteins ostreolysin (OlyA), pleurotolysin A (PlyA) and pleurotolysin B (PlyB). The present study of the native and recombinant proteins dissects out their lipid-binding characteristics and their roles in lipid binding and membrane permeabilization. Using lipid-binding studies, permeabilization of erythrocytes, large unilamellar vesicles of various lipid compositions, and electron microscopy, we show that OlyA, a PlyA homolog, preferentially binds to membranes rich in sterol and sphingomyelin, but it does not permeabilize them. The N-terminally truncated Δ48PlyB corresponds to the mature and active form of native PlyB, and it has a membrane attack complex-perforin (MACPF) domain. Δ48PlyB spontaneously oligomerizes in solution, and binds weakly to various lipid membranes but is not able to perforate them. However, binding of Δ48PlyB to the cholesterol and sphingomyelin membranes, and consequently, their permeabilization is dramatically promoted in the presence of OlyA. On these membranes, Δ48PlyB and OlyA form predominantly 13-meric oligomers. These are rosette-like structures with a thickness of ∼9 nm from the membrane surface, with 19.7 nm and 4.9 nm outer and inner diameters, respectively. When present on opposing vesicle membranes, these oligomers can dimerize and thus promote aggregation of vesicles. Based on the structural and functional characteristics of Δ48PlyB, we suggest that it shares some features with MACPF/cholesterol-dependent cytolysin (CDC) proteins. OlyA is obligatory for the Δ48PlyB permeabilization of membranes rich in cholesterol and sphingomyelin. 相似文献