全文获取类型
收费全文 | 2299篇 |
免费 | 226篇 |
国内免费 | 78篇 |
出版年
2024年 | 7篇 |
2023年 | 64篇 |
2022年 | 91篇 |
2021年 | 101篇 |
2020年 | 117篇 |
2019年 | 128篇 |
2018年 | 111篇 |
2017年 | 80篇 |
2016年 | 73篇 |
2015年 | 85篇 |
2014年 | 149篇 |
2013年 | 183篇 |
2012年 | 99篇 |
2011年 | 111篇 |
2010年 | 67篇 |
2009年 | 86篇 |
2008年 | 78篇 |
2007年 | 111篇 |
2006年 | 111篇 |
2005年 | 74篇 |
2004年 | 68篇 |
2003年 | 68篇 |
2002年 | 64篇 |
2001年 | 50篇 |
2000年 | 32篇 |
1999年 | 26篇 |
1998年 | 36篇 |
1997年 | 40篇 |
1996年 | 25篇 |
1995年 | 44篇 |
1994年 | 22篇 |
1993年 | 16篇 |
1992年 | 14篇 |
1991年 | 8篇 |
1990年 | 10篇 |
1989年 | 10篇 |
1988年 | 9篇 |
1987年 | 9篇 |
1986年 | 8篇 |
1985年 | 17篇 |
1984年 | 16篇 |
1983年 | 19篇 |
1982年 | 19篇 |
1981年 | 19篇 |
1980年 | 11篇 |
1979年 | 6篇 |
1978年 | 6篇 |
1977年 | 2篇 |
1975年 | 2篇 |
1973年 | 1篇 |
排序方式: 共有2603条查询结果,搜索用时 15 毫秒
141.
Cyclooxygenase-2 is a very important physiological enzyme playing key roles in various biological functions especially in the mechanism of pain and inflammation, among other roles, making it a molecule of high interest to the pharmaceutical community as a target. COX 2 enzyme is induced only during inflammatory processes or cancer and reflects no role in the guarding stomach lining. Thus, selective COX-2 inhibition can significantly reduce the adverse effects including GI tract damage and hepatotoxic effects of traditional NSAIDs like aspirin, ibuprofen, etc. Recent developments on COX-2 inhibitors is primarily focused on improving the selectivity index of the drug towards COX-2 along with enhancing the potency of the drug by modifying the scaffolds of Coxibs currently in the market like Celecoxib, Indomethacin, Oxaprozin, etc. We have reported the progress on new COX-2 inhibitors in the last decade (2008–2019) focussing on five heterocyclic rings- Pyrazole, Indole, Oxazole, Pyridine and Pyrrole. The addition of various moieties to these core rings and their structure-activity relationship along with their molecular modelling data have been explored in the article. This review aims to aid medicinal chemists in the design and discovery of better COX-2 inhibitors constructed on these five heterocyclic pharmacophores. 相似文献
142.
Adam C. Naj Honghuang Lin Badri N. Vardarajan Simon White Daniel Lancour Yiyi Ma Michael Schmidt Fangui Sun Mariusz Butkiewicz William S. Bush Brian W. Kunkle John Malamon Najaf Amin Seung Hoan Choi Kara L. Hamilton-Nelson Sven J. van der Lee Namrata Gupta Daniel C. Koboldt Anita L. DeStefano 《Genomics》2019,111(4):808-818
The Alzheimer's Disease Sequencing Project (ADSP) performed whole genome sequencing (WGS) of 584 subjects from 111 multiplex families at three sequencing centers. Genotype calling of single nucleotide variants (SNVs) and insertion-deletion variants (indels) was performed centrally using GATK-HaplotypeCaller and Atlas V2. The ADSP Quality Control (QC) Working Group applied QC protocols to project-level variant call format files (VCFs) from each pipeline, and developed and implemented a novel protocol, termed “consensus calling,” to combine genotype calls from both pipelines into a single high-quality set. QC was applied to autosomal bi-allelic SNVs and indels, and included pipeline-recommended QC filters, variant-level QC, and sample-level QC. Low-quality variants or genotypes were excluded, and sample outliers were noted. Quality was assessed by examining Mendelian inconsistencies (MIs) among 67 parent-offspring pairs, and MIs were used to establish additional genotype-specific filters for GATK calls. After QC, 578 subjects remained. Pipeline-specific QC excluded ~12.0% of GATK and 14.5% of Atlas SNVs. Between pipelines, ~91% of SNV genotypes across all QCed variants were concordant; 4.23% and 4.56% of genotypes were exclusive to Atlas or GATK, respectively; the remaining ~0.01% of discordant genotypes were excluded. For indels, variant-level QC excluded ~36.8% of GATK and 35.3% of Atlas indels. Between pipelines, ~55.6% of indel genotypes were concordant; while 10.3% and 28.3% were exclusive to Atlas or GATK, respectively; and ~0.29% of discordant genotypes were. The final WGS consensus dataset contains 27,896,774 SNVs and 3,133,926 indels and is publicly available. 相似文献
143.
Guoxi Li Yinli Zhao Yuanfang Li Yi Chen Wenjiao Jin Guirong Sun Ruili Han Yadong Tian Hong Li Xiangtao Kang 《Journal of cellular biochemistry》2019,120(8):13625-13639
144.
145.
146.
Cecilia Nigro Alessia Leone Michele Longo Immacolata Prevenzano Thomas H. Fleming Antonella Nicolò Luca Parrillo Rosa Spinelli Pietro Formisano Peter P. Nawroth Francesco Beguinot Claudia Miele 《生物化学与生物物理学报:疾病的分子基础》2019,1865(1):73-85
Impaired angiogenesis leads to long-term complications and is a major contributor of the high morbidity in patients with Diabetes Mellitus (DM). Methylglyoxal (MGO) is a glycolysis byproduct that accumulates in DM and is detoxified by the Glyoxalase 1 (Glo1). Several studies suggest that MGO contributes to vascular complications through mechanisms that remain to be elucidated. In this study we have clarified for the first time the molecular mechanism involved in the impairment of angiogenesis induced by MGO accumulation.Angiogenesis was evaluated in mouse aortic endothelial cells isolated from Glo1-knockdown mice (Glo1KD MAECs) and their wild-type littermates (WT MAECs). Reduction in Glo1 expression led to an accumulation of MGO and MGO-modified proteins and impaired angiogenesis of Glo1KD MAECs. Both mRNA and protein levels of the anti-angiogenic HoxA5 gene were increased in Glo1KD MAECs and its silencing improved both their migration and invasion. Nuclear NF-?B-p65 was increased 2.5-fold in the Glo1KD as compared to WT MAECs. Interestingly, NF-?B-p65 binding to HoxA5 promoter was also 2-fold higher in Glo1KD MAECs and positively regulated HoxA5 expression in MAECs. Consistent with these data, both the exposure to a chemical inhibitor of Glo1 “SpBrBzGSHCp2” (GI) and to exogenous MGO led to the impairment of migration and the increase of HoxA5 mRNA and NF-?B-p65 protein levels in microvascular mouse coronary endothelial cells (MCECs).This study demonstrates, for the first time, that MGO accumulation increases the antiangiogenic factor HoxA5 via NF-?B-p65, thereby impairing the angiogenic ability of endothelial cells. 相似文献
147.
Maria Isabel Mendona Eva Henriques Sofia Borges Ana Clia Sousa Andreia Pereira Marina Santos Margarida Temtem Snia Freitas Joel Monteiro Joo Adriano Sousa Ricardo Rodrigues Graa Guerra Roberto Palma dos Reis 《Genetics and molecular biology》2021,44(2)
The inclusion of a genetic risk score (GRS) can modify the risk prediction of coronary artery disease (CAD), providing an advantage over the use of traditional models. The predictive value of the genetic information on the recurrence of major adverse cardiovascular events (MACE) remains controversial. A total of 33 genetic variants previously associated with CAD were genotyped in 1587 CAD patients from the GENEMACOR study. Of these, 18 variants presented an hazard ratio >1, so they were selected to construct a weighted GRS (wGRS). MACE discrimination and reclassification were evaluated by C-Statistic, Net Reclassification Index and Integrated Discrimination Improvement methodologies. After the addition of wGRS to traditional predictors, the C-index increased from 0.566 to 0.572 (p=0.0003). Subsequently, adding wGRS to traditional plus clinical risk factors, this model slightly improved from 0.620 to 0.622 but with statistical significance (p=0.004). NRI showed that 17.9% of the cohort was better reclassified when the primary model was associated with wGRS. The Kaplan-Meier estimator showed that, at 15-year follow-up, the group with a higher number of risk alleles had a significantly higher MACE occurrence (p=0.011). In CAD patients, wGRS improved MACE risk prediction, discrimination and reclassification over the conventional factors, providing better cost-effective therapeutic strategies. 相似文献
148.
R. Tian W. S. Pitchford C. A. Morris N. G. Cullen C. D. K. Bottema 《Animal genetics》2010,41(3):253-259
β, β‐carotene‐9′, 10′‐dioxygenase (BCO2) plays a role in cleaving β‐carotene eccentrically, and may be involved in the control of adipose and milk colour in cattle. The bovine BCO2 gene was sequenced as a potential candidate gene for a beef fat colour QTL on chromosome (BTA) 15. A single nucleotide base change located in exon 3 causes the substitution of a stop codon (encoded by the A allele) for tryptophan80 (encoded by the G allele) (c. 240G>A, p.Trp80stop, referred to herein as SNP W80X). Association analysis showed significant differences in subcutaneous fat colour and beta‐carotene concentration amongst cattle with different BCO2 genotypes. Animals with the BCO2 AA genotype had more yellow beef fat and a higher beta‐carotene concentration in adipose tissues than those with the GA or GG genotype. QTL mapping analysis with the BCO2 SNP W80X fitted as a fixed effect confirmed that this SNP is likely to represent the quantitative trait nucleotide (QTN) for the fat colour‐related traits on BTA 15. Moreover, animals with the AA genotype had yellower milk colour and a higher concentration of beta‐carotene in the milk. 相似文献
149.
Oldich Nedvd Piotr Ceryngier Magdalena Hodková Ivo Hodek 《Entomologia Experimentalis et Applicata》2001,99(3):371-380
Two flight parameters (take-off and duration) and respiration level were measured, in two years in summer and early autumn, in dormant Coccinella septempunctata L. (Coleoptera: Coccinellidae) collected while hidden in grass tussocks in hibernation sites (HID) and in beetles collected on plants (PLA). The duration of tethered flight of HID beetles measured in the laboratory in late August and September 1995 (range of geometric means 190–440 s) was slightly longer than the flight of PLA beetles (80–310 s), both being much longer than trivial flight recorded in beetles foraging for prey during the breeding season (35 s). In general, the flight performance had a tendency to increase in September and to decrease in October.The oxygen consumption in HID beetles increased throughout September 1994 from 430 to 780 l g–1 h–1 and throughout October 1995 from 710 to 1060 l g–1 h–1. This increase is ascribed to a concomitant decrease in diapause intensity. A similar increase was observed also in PLA beetles in 1994 and oxygen consumption was always higher than in HID beetles, most probably due to feeding and digestion in PLA beetles.Laboratory feeding of HID beetles on aphids induced maturation of ovaries and increased oxygen uptake (from 680 to 1110 l g–1 h–1). Feeding on honey and pollen left their oxygen uptake unchanged. Effect of feeding on the flight parameters was mostly not significant. In agreement with its less suitable body shape and usually less distant dormancy sites, C. septempunctata was found a less apt flier than long-distance migrating coccinellid species. 相似文献
150.
Ploutz-Snyder L Foley J Ploutz-Snyder R Kanaley J Sagendorf K Meyer R 《European journal of applied physiology and occupational physiology》1999,79(3):212-220
Magnetic resonance imaging (MRI) was used to characterize the volumes and rates of gastric emptying of both liquid and gas following the ingestion of beverages of varying carbonation and carbohydrate levels. Eight subjects drank 800 ml each of four test beverages in a counterbalanced order: water, a non-carbonated carbohydrate-electrolyte solution (NC), a lightly carbonated carbohydrate-electrolyte solution (PC), and a carbonated cola (CC). T2-weighted, echoplanar images (25-30 contiguous slices, 1 cm thick, 256 x 128 matrix, TE = 80, 40 cm FOV) of the abdomen were collected at minutes 3,110, 20, 30, 45, and 60 following beverage ingestion. Images were analyzed for gas and liquid volumes. Water and NC emptied the most rapidly, with half times of 21(3) and 31(3) min, respectively [mean (SE)]. PC emptied significantly slower [47 (6) min] and CC slower yet [107 (8) min]. The carbonation content of the beverage accounted for 84% of the variation in emptying time, whereas carbohydrate content did not account for any significant variation. The gastric gas volume of the CC was higher at 2 min post-ingestion compared with all other drinks; however, the rate of emptying of the gas was the same among all beverages. Significantly greater total gastric volumes (gas+ liquid) were associated with the ingestion of CC, and accordingly produced a greater severity of gastric distress, as evaluated with a gastric distress inventory. The high gastric gas volumes (approximately 600 ml) after ingestion of CC suggested a potential source of error in body composition using standard hydrostatic weighing methods. This prediction was tested in nine additional subjects. Ingestion of 800 ml of CC prior to hydrostatic weighing resulted in a 0.7% underestimate of body density and thus an 11% overestimate of percentage body fat compared to measurements made before beverage consumption. 相似文献