全文获取类型
收费全文 | 3312篇 |
免费 | 294篇 |
国内免费 | 4篇 |
专业分类
3610篇 |
出版年
2023年 | 17篇 |
2022年 | 33篇 |
2021年 | 55篇 |
2020年 | 35篇 |
2019年 | 34篇 |
2018年 | 42篇 |
2017年 | 41篇 |
2016年 | 94篇 |
2015年 | 162篇 |
2014年 | 184篇 |
2013年 | 213篇 |
2012年 | 251篇 |
2011年 | 269篇 |
2010年 | 175篇 |
2009年 | 162篇 |
2008年 | 190篇 |
2007年 | 215篇 |
2006年 | 207篇 |
2005年 | 201篇 |
2004年 | 184篇 |
2003年 | 162篇 |
2002年 | 165篇 |
2001年 | 38篇 |
2000年 | 25篇 |
1999年 | 25篇 |
1998年 | 51篇 |
1997年 | 30篇 |
1996年 | 32篇 |
1995年 | 31篇 |
1994年 | 15篇 |
1993年 | 31篇 |
1992年 | 16篇 |
1991年 | 23篇 |
1990年 | 18篇 |
1989年 | 8篇 |
1988年 | 15篇 |
1987年 | 15篇 |
1986年 | 18篇 |
1985年 | 6篇 |
1984年 | 19篇 |
1983年 | 13篇 |
1982年 | 19篇 |
1981年 | 19篇 |
1980年 | 6篇 |
1979年 | 5篇 |
1978年 | 4篇 |
1973年 | 5篇 |
1972年 | 8篇 |
1971年 | 6篇 |
1970年 | 6篇 |
排序方式: 共有3610条查询结果,搜索用时 0 毫秒
71.
Catherine M. Phillips Audrey C. Tierney Pablo Perez‐Martinez Catherine Defoort Ellen E. Blaak Ingrid M. F. Gjelstad Jose Lopez‐Miranda Malgorzata Kiec‐Klimczak Malgorzata Malczewska‐Malec Christian A. Drevon Wendy Hall Julie A. Lovegrove Brita Karlstrom Ulf Risérus Helen M. Roche 《Obesity (Silver Spring, Md.)》2013,21(1):E154-E161
Objective:
Obesity is a key factor in the development of the metabolic syndrome (MetS), which is associated with increased cardiometabolic risk. We investigated whether obesity classification by BMI and body fat percentage (BF%) influences cardiometabolic profile and dietary responsiveness in 486 MetS subjects (LIPGENE dietary intervention study).Design and Methods:
Anthropometric measures, markers of inflammation and glucose metabolism, lipid profiles, adhesion molecules, and hemostatic factors were determined at baseline and after 12 weeks of four dietary interventions (high saturated fat (SFA), high monounsaturated fat (MUFA), and two low fat high complex carbohydrate (LFHCC) diets, one supplemented with long chain n‐3 polyunsaturated fatty acids (LC n‐3 PUFAs)).Results:
About 39 and 87% of subjects classified as normal and overweight by BMI were obese according to their BF%. Individuals classified as obese by BMI (≥30 kg/m2) and BF% (≥25% (men) and ≥35% (women)) (OO, n = 284) had larger waist and hip measurements, higher BMI and were heavier (P < 0.001) than those classified as nonobese by BMI but obese by BF% (NOO, n = 92). OO individuals displayed a more proinflammatory (higher C reactive protein (CRP) and leptin), prothrombotic (higher plasminogen activator inhibitor‐1 (PAI‐1)), proatherogenic (higher leptin/adiponectin ratio) and more insulin resistant (higher HOMA‐IR) metabolic profile relative to the NOO group (P < 0.001). Interestingly, tumor necrosis factor‐α (TNF‐α) concentrations were lower post‐intervention in NOO individuals compared with OO subjects (P < 0.001).Conclusions:
In conclusion, assessing BF% and BMI as part of a metabotype may help to identify individuals at greater cardiometabolic risk than BMI alone. 相似文献72.
Wendy W. J. de Leng Christa G. Gadellaa-van Hooijdonk Fran?oise A. S. Barendregt-Smouter Marco J. Koudijs Ies Nijman John W. J. Hinrichs Edwin Cuppen Stef van Lieshout Robert D. Loberg Maja de Jonge Emile E. Voest Roel A. de Weger Neeltje Steeghs Marlies H. G. Langenberg Stefan Sleijfer Stefan M. Willems Martijn P. Lolkema 《PloS one》2016,11(2)
Background
Targeted Next Generation Sequencing (NGS) offers a way to implement testing of multiple genetic aberrations in diagnostic pathology practice, which is necessary for personalized cancer treatment. However, no standards regarding input material have been defined. This study therefore aimed to determine the effect of the type of input material (e.g. formalin fixed paraffin embedded (FFPE) versus fresh frozen (FF) tissue) on NGS derived results. Moreover, this study aimed to explore a standardized analysis pipeline to support consistent clinical decision-making.Method
We used the Ion Torrent PGM sequencing platform in combination with the Ion AmpliSeq Cancer Hotspot Panel v2 to sequence frequently mutated regions in 50 cancer related genes, and validated the NGS detected variants in 250 FFPE samples using standard diagnostic assays. Next, 386 tumour samples were sequenced to explore the effect of input material on variant detection variables. For variant calling, Ion Torrent analysis software was supplemented with additional variant annotation and filtering.Results
Both FFPE and FF tissue could be sequenced reliably with a sensitivity of 99.1%. Validation showed a 98.5% concordance between NGS and conventional sequencing techniques, where NGS provided both the advantage of low input DNA concentration and the detection of low-frequency variants. The reliability of mutation analysis could be further improved with manual inspection of sequence data.Conclusion
Targeted NGS can be reliably implemented in cancer diagnostics using both FFPE and FF tissue when using appropriate analysis settings, even with low input DNA. 相似文献73.
Glenn Salkeld Michelle Cunich Jack Dowie Kirsten Howard Manish I. Patel Graham Mann Wendy Lipworth 《PloS one》2016,11(4)
ImportanceDecision support tools can assist people to apply population-based evidence on benefits and harms to individual health decisions. A key question is whether “personalising” choice within decisions aids leads to better decision quality.ObjectiveTo assess the effect of personalising the content of a decision aid for prostate cancer screening using the Prostate Specific Antigen (PSA) test.DesignRandomized controlled trial.SettingAustralia.Participants1,970 men aged 40–69 years were approached to participate in the trial.Intervention1,447 men were randomly allocated to either a standard decision aid with a fixed set of five attributes or a personalised decision aid with choice over the inclusion of up to 10 attributes.Results5% of men in the fixed attribute group scored ‘Have a PSA test’ as the opinion generated by the aid, as compared to 62% of men in the personalised choice group (χ2 = 569.38, 2df, p< 0001). Those men who used the personalised decision aid had slightly higher decision quality (t = 2.157, df = 1444, p = 0.031). The men in the personalised choice group made extensive use of the additional decision attributes. There was no difference between the two groups in terms of their stated intention to undergo screening in the next 12 months.ConclusionsTogether, these findings suggest that personalised decision support systems could be an important development in shared decision-making and patient-centered care.
Trial Registration
Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12612000723886 相似文献74.
Natalia J. Martinez Ganesha Rai Adam Yasgar Wendy A. Lea Hongmao Sun Yuhong Wang Diane K. Luci Shyh-Ming Yang Kana Nishihara Shunichi Takeda Mohiuddin Irina Earnshaw Tetsuya Okada Kazutoshi Mori Kelli Wilson Gregory J. Riggins Menghang Xia Maurizio Grimaldi Ajit Jadhav David J. Maloney Anton Simeonov 《PloS one》2016,11(11)
75.
76.
77.
In mammals, paternal and maternal pronuclei undergo profound chromatin reorganisation upon fertilisation. How these events
are orchestrated within centromeric regions to ensure proper chromosome segregation in the following cellular divisions is
unknown. In this study, we followed the dynamic unfolding of the centromeric regions, i.e. the centric and pericentric satellite
repeats, by DNA fluorescent in situ hybridization (FISH) during the first cell cycle up to the two-cell stage. The distinct
chromatin from female and male gametes both undergo rapid remodelling and reach a zygotic organisation in which the satellites
occupy restricted spatial domains surrounding the nucleolar precursor body. A transition from this zygotic to a somatic cell-like
organisation takes place during the two-cell stage. Using 3D immuno-FISH, we find that, whereas maternal pericentric regions
are marked with H3K9me3, H4K20me3 and HP1β, paternal ones only showed HP1β marking. Thus, despite different chromatin features,
male and female pronuclei organise their centromeric regions in the same way within the nuclei to align chromosomes on the
metaphase plate and segregate them appropriately. Our findings highlight the importance of ensuring a proper centromere function
while preserving the distinction of parental genome origin during the return to totipotency in the zygote.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
78.
Tymchuk WE Sundström LF Devlin RH 《Evolution; international journal of organic evolution》2007,61(5):1225-1237
The purpose of this study was to examine, using a rainbow trout (Oncorhynchus mykiss) model system, the fitness consequences of three generations of introgression of genotypes adapted to two different environments (culture and nature). The experiments also isolated the influence of competitive interactions and risk of predation on the relative growth and survival of the wild and backcrossed lines. Line crosses representing fast-growing pure domestic (D), slow-growing pure wild (W), domestic x wild hybrids (F1), F1 x wild backcrosses (B1), and B1 x wild backcrosses (B2) were generated and reared under (1) culture conditions, (2) seminatural conditions with competition among genotypes, and (3) seminatural conditions under risk of predation. Survival of the fry in a seminatural environment with competition fit an additive model of gene action with the domestic fish having the highest survival and the wild fish the lowest, but under risk of predation outbreeding depression was suggested by low survival of the B2 lines. Evidence of a trade-off in growth and survival under risk of predation along with observations of genetically determined behavioral differences among the strains may provide some explanation for the observed differences in survival among the strains. This information is relevant to improving our evolutionary understanding of the interaction among genomes, and the influence of environment, during hybridization events. Results from this experiment indicate that alteration of phenotype likely played a prominent role in the reduced fitness experienced by progeny produced after three generations of introgression, supporting the theory that disruption of genotypes selected for adaptation to local conditions may be a primary cause of outbreeding depression in species such as salmon. 相似文献
79.
80.
Woods WS Boettcher JM Zhou DH Kloepper KD Hartman KL Ladror DT Qi Z Rienstra CM George JM 《The Journal of biological chemistry》2007,282(47):34555-34567
Alpha-synuclein (AS) is an intrinsically unstructured protein in aqueous solution but is capable of forming beta-sheet-rich fibrils that accumulate as intracytoplasmic inclusions in Parkinson disease and certain other neurological disorders. However, AS binding to phospholipid membranes leads to a distinct change in protein conformation, stabilizing an extended amphipathic alpha-helical domain reminiscent of the exchangeable apolipoproteins. To better understand the significance of this conformational change, we devised a novel bacteriophage display screen to identify protein binding partners of helical AS and have identified 20 proteins with roles in diverse cellular processes related to membrane trafficking, ion channel modulation, redox metabolism, and gene regulation. To verify that the screen identifies proteins with specificity for helical AS, we further characterized one of these candidates, endosulfine alpha (ENSA), a small cAMP-regulated phosphoprotein implicated in the regulation of insulin secretion but also expressed abundantly in the brain. We used solution NMR to probe the interaction between ENSA and AS on the surface of SDS micelles. Chemical shift perturbation mapping experiments indicate that ENSA interacts specifically with residues in the N-terminal helical domain of AS in the presence of SDS but not in aqueous buffer lacking SDS. The ENSA-related protein ARPP-19 (cAMP-regulated phosphoprotein 19) also displays specific interactions with helical AS. These results confirm that the helical N terminus of AS can mediate specific interactions with other proteins and suggest that membrane binding may regulate the physiological activity of AS in vivo. 相似文献