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141.
Yu S. Zhou Sheila Webb Laura Lettice Steve Tardif Fiona Kilanowski Christine Tyrrell Heather MacPherson Fiona Semple Peter Tennant Tina Baker Alan Hart Paul Devenney Paul Perry Tracey Davey Perdita Barran Chris L. Barratt Julia R. Dorin 《PLoS genetics》2013,9(10)
β-defensin peptides are a family of antimicrobial peptides present at mucosal surfaces, with the main site of expression under normal conditions in the male reproductive tract. Although they kill microbes in vitro and interact with immune cells, the precise role of these genes in vivo remains uncertain. We show here that homozygous deletion of a cluster of nine β-defensin genes (DefbΔ9) in the mouse results in male sterility. The sperm derived from the mutants have reduced motility and increased fragility. Epididymal sperm isolated from the cauda should require capacitation to induce the acrosome reaction but sperm from the mutants demonstrate precocious capacitation and increased spontaneous acrosome reaction compared to wild-types but have reduced ability to bind the zona pellucida of oocytes. Ultrastructural examination reveals a defect in microtubule structure of the axoneme with increased disintegration in mutant derived sperm present in the epididymis cauda region, but not in caput region or testes. Consistent with premature acrosome reaction, sperm from mutant animals have significantly increased intracellular calcium content. Thus we demonstrate in vivo that β-defensins are essential for successful sperm maturation, and their disruption leads to alteration in intracellular calcium, inappropriate spontaneous acrosome reaction and profound male infertility. 相似文献
142.
Katherine R. Bull Andrew J. Rimmer Owen M. Siggs Lisa A. Miosge Carla M. Roots Anselm Enders Edward M. Bertram Tanya L. Crockford Belinda Whittle Paul K. Potter Michelle M. Simon Ann-Marie Mallon Steve D. M. Brown Bruce Beutler Christopher C. Goodnow Gerton Lunter Richard J. Cornall 《PLoS genetics》2013,9(1)
Forward genetics screens with N-ethyl-N-nitrosourea (ENU) provide a powerful way to illuminate gene function and generate mouse models of human disease; however, the identification of causative mutations remains a limiting step. Current strategies depend on conventional mapping, so the propagation of affected mice requires non-lethal screens; accurate tracking of phenotypes through pedigrees is complex and uncertain; out-crossing can introduce unexpected modifiers; and Sanger sequencing of candidate genes is inefficient. Here we show how these problems can be efficiently overcome using whole-genome sequencing (WGS) to detect the ENU mutations and then identify regions that are identical by descent (IBD) in multiple affected mice. In this strategy, we use a modification of the Lander-Green algorithm to isolate causative recessive and dominant mutations, even at low coverage, on a pure strain background. Analysis of the IBD regions also allows us to calculate the ENU mutation rate (1.54 mutations per Mb) and to model future strategies for genetic screens in mice. The introduction of this approach will accelerate the discovery of causal variants, permit broader and more informative lethal screens to be used, reduce animal costs, and herald a new era for ENU mutagenesis. 相似文献
143.
Guang Sun Farrell Cahill Wayne Gulliver Yanqing Yi Yagang Xie Tracey Bridger David Pace Hongwei Zhang 《Obesity (Silver Spring, Md.)》2013,21(3):499-503
Background:
Body adiposity index (BAI), indirect method proposed to predict adiposity, was developed using Mexican Americans and very little data are available regarding its validation in Caucasian populations to date.Objective:
The study objectives were to validate the BAI with dual‐energy X‐ray absorptiometry (DXA) body fat percentage (%BF), taking into consideration the gender and adiposity status.Design and Methods:
A total of 2,601 subjects (Male 662, Female 1939) from our Complex Diseases in the Newfoundland population: Environment and Genetics (CODING) study participated in this investigation. Pearson correlations, with the entire cohort along with men and women separately, were used to compare the correlation of both BAI and BMI with %BF. Additionally, the concordance between BAI and BMI with %BF were also performed among normal‐weight (NW), overweight (OW), and obese (OB) groups. Adiposity status was determined by the Bray Criteria according to DXA %BF.Results:
BAI performs better than BMI in our Caucasian population by: (1) reflecting the gender difference in total %BF between women and men, (2) correlating better with DXA %BF than BMI when women and men are combined, and (3) performing better in NW and OW subjects for both the sexes. However, BAI performs less effectively than BMI in OB men and women.Conclusion:
In summary, the BAI method is a better estimate of adiposity than BMI in non‐OB subjects in our Caucasian population. A measurement sensitive to the changes in adiposity for both men and women is suggested to be incorporated into the present BAI equation to increase accuracy. 相似文献144.
145.
Candy Kumps Annelies Fieuw Pieter Mestdagh Bj?rn Menten Steve Lefever Filip Pattyn Sara De Brouwer Tom Sante Johannes Hubertus Schulte Alexander Schramm Nadine Van Roy Tom Van Maerken Rosa Noguera Valérie Combaret Christine Devalck Frank Westermann Geneviève Laureys Angelika Eggert Jo Vandesompele Katleen De Preter Frank Speleman 《PloS one》2013,8(1)
Neuroblastoma is an embryonic tumor arising from immature sympathetic nervous system cells. Recurrent genomic alterations include MYCN and ALK amplification as well as recurrent patterns of gains and losses of whole or large partial chromosome segments. A recent whole genome sequencing effort yielded no frequently recurring mutations in genes other than those affecting ALK. However, the study further stresses the importance of DNA copy number alterations in this disease, in particular for genes implicated in neuritogenesis. Here we provide additional evidence for the importance of focal DNA copy number gains and losses, which are predominantly observed in MYCN amplified tumors. A focal 5 kb gain encompassing the MYCN regulated miR-17∼92 cluster as sole gene was detected in a neuroblastoma cell line and further analyses of the array CGH data set demonstrated enrichment for other MYCN target genes in focal gains and amplifications. Next we applied an integrated genomics analysis to prioritize MYCN down regulated genes mediated by MYCN driven miRNAs within regions of focal heterozygous or homozygous deletion. We identified RGS5, a negative regulator of G-protein signaling implicated in vascular normalization, invasion and metastasis, targeted by a focal homozygous deletion, as a new MYCN target gene, down regulated through MYCN activated miRNAs. In addition, we expand the miR-17∼92 regulatory network controlling TGFß signaling in neuroblastoma with the ring finger protein 11 encoding gene RNF11, which was previously shown to be targeted by the miR-17∼92 member miR-19b. Taken together, our data indicate that focal DNA copy number imbalances in neuroblastoma (1) target genes that are implicated in MYCN signaling, possibly selected to reinforce MYCN oncogene addiction and (2) serve as a resource for identifying new molecular targets for treatment. 相似文献
146.
Farrell Cahill Mariam Shahidi Jennifer Shea Danny Wadden Wayne Gulliver Edward Randell Sudesh Vasdev Guang Sun 《PloS one》2013,8(3)
Background
Magnesium plays a role in glucose and insulin homeostasis and evidence suggests that magnesium intake is associated with insulin resistance (IR). However, data is inconsistent and most studies have not adequately controlled for critical confounding factors.Objective
The study investigated the association between magnesium intake and IR in normal-weight (NW), overweight (OW) and obese (OB) along with pre- and post- menopausal women.Design
A total of 2295 subjects (590 men and 1705 women) were recruited from the CODING study. Dietary magnesium intake was computed from the Willett Food Frequency Questionnaire (FFQ). Adiposity (NW, OW and OB) was classified by body fat percentage (%BF) measured by Dual-energy X-ray absorptiometry according to the Bray criteria. Multiple regression analyses were used to test adiposity-specific associations of dietary magnesium intake on insulin resistance adjusting for caloric intake, physical activity, medication use and menopausal status.Results
Subjects with the highest intakes of dietary magnesium had the lowest levels of circulating insulin, HOMA-IR, and HOMA-ß and subjects with the lowest intake of dietary magnesium had the highest levels of these measures, suggesting a dose effect. Multiple regression analysis revealed a strong inverse association between dietary magnesium with IR. In addition, adiposity and menopausal status were found to be critical factors revealing that the association between dietary magnesium and IR was stronger in OW and OB along with Pre-menopausal women.Conclusion
The results of this study indicate that higher dietary magnesium intake is strongly associated with the attenuation of insulin resistance and is more beneficial for overweight and obese individuals in the general population and pre-menopausal women. Moreover, the inverse correlation between insulin resistance and dietary magnesium intake is stronger when adjusting for %BF than BMI. 相似文献147.
Emily R. Winter Andrew M. Hindes Steve Lane J. Robert Britton 《Journal of fish biology》2020,97(4):1209-1219
Biotelemetry is a central tool for fisheries management, with the implantation of transmitters into animals requiring refined surgical techniques that maximize retention rates and fish welfare. Even following successful surgery, long-term post-release survival rates can vary considerably, although knowledge is limited for many species. The aim here was to investigate the post-tagging survival rates in the wild of two lowland river fish species, common bream Abramis brama and northern pike Esox lucius, following their intra-peritoneal double-tagging with acoustic transmitters and passive integrated transponder (PIT) tags. Survival over a 2-year period was assessed using acoustic transmitter data in Cox proportional hazards models. Post-tagging survival rates were lowest in the reproductive periods of both species, but in bream, fish tagged just prior to spawning actually had the highest subsequent survival rates. Pike survival was influenced by sex, with males generally surviving longer than females. PIT tag detections at fixed stations identified bream that remained active, despite loss of an acoustic transmitter signal. In these instances, loss of the acoustic signal occurred up to 215 days post-tagging and only during late spring or summer, indicating a role of elevated temperature, while PIT detections occurred between 18 and 359 days after the final acoustic detections. Biotelemetry studies must thus always consider the date of tagging as a fundamental component of study designs to avoid tagged fish having premature end points within telemetry studies. 相似文献
148.
Lie Maria E. K. Kickinger Stefanie Skovgaard-Petersen Jonas Ecker Gerhard F. Clausen Rasmus P. Schousboe Arne White H. Steve Wellendorph Petrine 《Neurochemical research》2020,45(7):1551-1565
Neurochemical Research - Focal epileptic seizures can in some patients be managed by inhibiting γ-aminobutyric acid (GABA) uptake via the GABA transporter 1 (GAT1) using tiagabine... 相似文献
149.
The actinobacterial transcription factor RbpA binds to the principal sigma subunit of RNA polymerase
150.
Anbarasi Kothandapani Akshada Sawant Venkata Srinivas Mohan Nimai Dangeti Robert W. Sobol Steve M. Patrick 《Nucleic acids research》2013,41(15):7332-7343
Base excision repair (BER) and mismatch repair (MMR) pathways play an important role in modulating cis-Diamminedichloroplatinum (II) (cisplatin) cytotoxicity. In this article, we identified a novel mechanistic role of both BER and MMR pathways in mediating cellular responses to cisplatin treatment. Cells defective in BER or MMR display a cisplatin-resistant phenotype. Targeting both BER and MMR pathways resulted in no additional resistance to cisplatin, suggesting that BER and MMR play epistatic roles in mediating cisplatin cytotoxicity. Using a DNA Polymerase β (Polβ) variant deficient in polymerase activity (D256A), we demonstrate that MMR acts downstream of BER and is dependent on the polymerase activity of Polβ in mediating cisplatin cytotoxicity. MSH2 preferentially binds a cisplatin interstrand cross-link (ICL) DNA substrate containing a mismatch compared with a cisplatin ICL substrate without a mismatch, suggesting a novel mutagenic role of Polβ in activating MMR in response to cisplatin. Collectively, these results provide the first mechanistic model for BER and MMR functioning within the same pathway to mediate cisplatin sensitivity via non-productive ICL processing. In this model, MMR participation in non-productive cisplatin ICL processing is downstream of BER processing and dependent on Polβ misincorporation at cisplatin ICL sites, which results in persistent cisplatin ICLs and sensitivity to cisplatin. 相似文献