全文获取类型
收费全文 | 337篇 |
免费 | 15篇 |
专业分类
耳鼻咽喉 | 14篇 |
儿科学 | 22篇 |
妇产科学 | 6篇 |
基础医学 | 17篇 |
临床医学 | 17篇 |
内科学 | 68篇 |
皮肤病学 | 1篇 |
神经病学 | 25篇 |
特种医学 | 10篇 |
外科学 | 109篇 |
综合类 | 4篇 |
预防医学 | 7篇 |
眼科学 | 5篇 |
药学 | 17篇 |
中国医学 | 1篇 |
肿瘤学 | 29篇 |
出版年
2023年 | 8篇 |
2022年 | 9篇 |
2021年 | 4篇 |
2020年 | 3篇 |
2019年 | 11篇 |
2018年 | 3篇 |
2017年 | 6篇 |
2016年 | 9篇 |
2015年 | 10篇 |
2014年 | 15篇 |
2013年 | 18篇 |
2012年 | 16篇 |
2011年 | 20篇 |
2010年 | 12篇 |
2009年 | 3篇 |
2008年 | 15篇 |
2007年 | 12篇 |
2006年 | 20篇 |
2005年 | 28篇 |
2004年 | 12篇 |
2003年 | 17篇 |
2002年 | 11篇 |
2001年 | 4篇 |
2000年 | 5篇 |
1999年 | 5篇 |
1998年 | 2篇 |
1996年 | 3篇 |
1995年 | 5篇 |
1994年 | 2篇 |
1993年 | 4篇 |
1992年 | 5篇 |
1991年 | 6篇 |
1990年 | 9篇 |
1989年 | 6篇 |
1988年 | 2篇 |
1987年 | 4篇 |
1986年 | 4篇 |
1983年 | 2篇 |
1981年 | 1篇 |
1979年 | 2篇 |
1978年 | 2篇 |
1977年 | 1篇 |
1976年 | 2篇 |
1975年 | 2篇 |
1974年 | 1篇 |
1973年 | 3篇 |
1972年 | 2篇 |
1971年 | 1篇 |
1970年 | 2篇 |
1967年 | 1篇 |
排序方式: 共有352条查询结果,搜索用时 15 毫秒
61.
62.
63.
Jahanzaib Khwaja Joshua Bomsztyk Shameem Mahmood Brendan Wisniowski Raakhee Shah Anish Tailor Kwee Yong Rakesh Popat Neil Rabin Charalampia Kyriakou Jonathan Sive Simona Degli Esposti Daniel F. P. Larkin Sarah Worthington Alyse Hart Emma Dowling Nuno Correia Ceri Bygrave Andrzej Rydzewski Krzysztof Jamroziak Ashutosh D. Wechalekar 《Blood cancer journal》2022,12(9)
64.
Joel Frohlich Meghan T. Miller Lynne M. Bird Pilar Garces Hannah Purtell Marius C. Hoener Benjamin D. Philpot Michael S. Sidorov Wen-Hann Tan Maria-Clemencia Hernandez Alexander Rotenberg Shafali S. Jeste Michelle Krishnan Omar Khwaja Joerg F. Hipp 《Neuropsychopharmacology》2019,85(9):752-759
Background
Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by either disruptions of the gene UBE3A or deletion of chromosome 15 at 15q11-q13, which encompasses UBE3A and several other genes, including GABRB3, GABRA5, GABRG3, encoding gamma-aminobutyric acid type A receptor subunits (3, 5, 3). Individuals with deletions are generally more impaired than those with other genotypes, but the underlying pathophysiology remains largely unknown. Here, we used electroencephalography (EEG) to test the hypothesis that genes other than UBE3A located on 15q11-q13 cause differences in pathophysiology between AS genotypes.Methods
We compared spectral power of clinical EEG recordings from children (1–18 years of age) with a deletion genotype (n = 37) or a nondeletion genotype (n = 21) and typically developing children without Angelman syndrome (n = 48).Results
We found elevated theta power (peak frequency: 5.3 Hz) and diminished beta power (peak frequency: 23 Hz) in the deletion genotype compared with the nondeletion genotype as well as excess broadband EEG power (1–32 Hz) peaking in the delta frequency range (peak frequency: 2.8 Hz), shared by both genotypes but stronger for the deletion genotype at younger ages.Conclusions
Our results provide strong evidence for the contribution of non-UBE3A neuronal pathophysiology in deletion AS and suggest that hemizygosity of the GABRB3-GABRA5-GABRG3 gene cluster causes abnormal theta and beta EEG oscillations that may underlie the more severe clinical phenotype. Our work improves the understanding of AS pathophysiology and has direct implications for the development of AS treatments and biomarkers. 相似文献65.
Lazaros C. Foukas Inma M. Berenjeno Alexander Gray Asim Khwaja Bart Vanhaesebroeck 《Proceedings of the National Academy of Sciences of the United States of America》2010,107(25):11381-11386
Small molecule inhibitors of PI3K for oncology mainly target the class I PI3Ks, comprising the p110α, β, γ, and δ isoforms, of which only p110α is mutated in cancer. To assess the roles of class I PI3K isoforms in cell proliferation and survival, we generated immortalized mouse leukocyte and fibroblast models in which class I PI3Ks were inactivated by genetic and pharmacological approaches. In IL3-dependent hemopoietic progenitor cells (which express all four class I PI3K isoforms), genetic inactivation of either p110α or p110δ did not affect cell proliferation or survival or sensitize to p110β or p110γ inactivation. Upon compound inactivation of p110α and p110δ, which removed >90% of p85-associated PI3K activity, remarkably, cells continued to proliferate effectively, with p110β assuming an essential role in signaling and cell survival. Furthermore, under these conditions of diminished class I PI3K activity, input from the ERK pathway became important for cell survival. Similar observations were made in mouse embryonic fibroblasts (which mainly express p110α and p110β) in which p110α or p110β could sustain cell proliferation as a single isoform. Taken together, these data demonstrate that a small fraction of total class I PI3K activity is sufficient to sustain cell survival and proliferation. Persistent inhibition of selected PI3K isoforms can allow the remaining isoform(s) to couple to upstream signaling pathways in which they are not normally engaged. Such functional redundancy of class IA PI3K isoforms upon sustained PI3K inhibition has implications for the development and use of PI3K inhibitors in cancer. 相似文献
66.
67.
Asim Khwaja Ian E. Addison Beryl Johnson Kwee Yong David C. Linch 《British journal of haematology》1994,88(3):515-519
Summary. In addition to its haemopoietic effects, interleukin-3 (IL-3) enhances leucocyte function in vitro . In this study we examined the effects on haematological variables and monocyte function of a single IL-3 infusion in five haematologically normal individuals. There was a rapid fall in circulating monocyte (to 24 ± 6% of pre-infusion value) and eosinophil numbers (to 3 ± 2%) with a nadir at 30 min and gradual return to baseline over 6h. No significant changes in monocyte expression of the adhesion molecules CD11b or L-selectin or of monocyte respiratory burst activity were detected. There was a significant increase in monocyte phagocytosis and killing of Canadida after IL-3 infusion: the percentage of monocytes which had ingested Candida increased from 39 ± 10% to 62 ± 12% and the total number of Candida killed per 100 monocytes increased from 63 ± 34 to 210 ± 59 ( P < 0.05 and P < 0.01 respectively). There was no inhibition of neutrophil migration into a 'skin window' site and monocyte migration was moderately enhanced (peak increase of 260 ± 47%). These results show that IL-3 has significant effects on monocyte function in vivo and could be of use in augmenting host defence mechanisms in immunocompromised patients. 相似文献
68.
Human granulocyte-macrophage colony-stimulating factor (GM-CSF) increases neutrophil surface expression of the cellular adhesion molecule CD11b and primes the respiratory burst stimulated by the bacterial peptide f-met-leuphe (FMLP). We have examined the effects of the isoquinolinesulfonamide protein kinase inhibitors H7 and H8 on these functions of GM-CSF using whole blood assays. Concentrations of H7 and H8 that inhibited the 12-O-tetradecanoyl-phorbol-13-acetate (TPA) stimulated upregulation of CD11b expression and activation of the respiratory burst, both augmented the effects of GM-CSF. H7 and H8 enhanced the GM-CSF-stimulated increase in CD11b expression to 215% +/- 10% (P less than .05) and 233% +/- 45% (P less than .05), respectively, of the value obtained with GM-CSF alone. The GM-CSF priming of the FMLP-stimulated oxidative burst was increased to 190% +/- 44% (P less than .01) by preincubation with H7 and to 172% +/- 25% (P less than .01) with H8. Preincubation with H8 did not affect overall binding of 125I-GM-CSF to neutrophils, but inhibited GM-CSF receptor internalization after ligand binding (P less than .05). These data indicate that the effects of GM-CSF are not mediated by protein kinase C and that a phosphorylation event down-modulates the neutrophil response to GM-CSF. It suggests that internalization of the receptor-ligand complex is not a rate-limiting step in signal transduction, and that regulation of the rate of internalization may be an important level of control of the activity of GM-CSF. 相似文献
69.
The effects of rhGM-CSF on the neutrophil respiratory burst when studied in whole blood 总被引:2,自引:0,他引:2
Mervyn S. Jaswon Asim Khwaja Pamela J. Roberts H. Mark Jones David C. Linch 《British journal of haematology》1990,75(2):181-187
A simple semiquantitative cytofluorometric method has been developed for measuring neutrophil respiratory burst activity in whole blood samples. This technique avoids the introduction of laboratory artefacts which modulate neutrophil function. In addition, flow cytometric analysis allows the response to be studied in individual cells. We show here that neutrophils examined freshly ex vivo, exhibit only weak respiratory burst activity in response to stimulation with the chemotactic peptide FMLP (10(-6) M). Prior incubation with rhGM-CSF results in an increase in the number of responding cells from 13.5 +/- 2.36% (mean +/- SEM) to 46.7 +/- 6.3% (P less than 0.0001) with an increase in total respiratory burst activity of 567% (P = 0.001). The majority of neutrophils in whole blood (67.1 +/- 8.1%) exhibit respiratory burst activity in response to stimulation with phorbol ester (1 micrograms/ml of TPA), and this response is also significantly primed by rhGM-CSF (P = 0.004). The enhancement of respiratory burst activity induced by rhGM-CSF is due to both recruitment of previously unresponsive neutrophils, and to intensification of the response of the responding cells. In vivo administration of rhGM-CSF also results in priming of the respiratory burst in response to FMLP, although the enhancement of activity is not as great as that obtained when pre-infusion blood samples are incubated with rhGM-CSF in vitro. 相似文献
70.
Synteny perturbations between wheat homoeologous chromosomes caused by locus duplications and deletions correlate with recombination rates 总被引:16,自引:0,他引:16
Akhunov ED Akhunova AR Linkiewicz AM Dubcovsky J Hummel D Lazo G Chao S Anderson OD David J Qi L Echalier B Gill BS Miftahudin Gustafson JP La Rota M Sorrells ME Zhang D Nguyen HT Kalavacharla V Hossain K Kianian SF Peng J Lapitan NL Wennerlind EJ Nduati V Anderson JA Sidhu D Gill KS McGuire PE Qualset CO Dvorak J 《Proceedings of the National Academy of Sciences of the United States of America》2003,100(19):10836-10841
Loci detected by Southern blot hybridization of 3,977 expressed sequence tag unigenes were mapped into 159 chromosome bins delineated by breakpoints of a series of overlapping deletions. These data were used to assess synteny levels along homoeologous chromosomes of the wheat A, B, and D genomes, in relation to both bin position on the centromere-telomere axis and the gradient of recombination rates along chromosome arms. Synteny level decreased with the distance of a chromosome region from the centromere. It also decreased with an increase in recombination rates along the average chromosome arm. There were twice as many unique loci in the B genome than in the A and D genomes, and synteny levels between the B genome chromosomes and the A and D genome homoeologues were lower than those between the A and D genome homoeologues. These differences among the wheat genomes were attributed to differences in the mating systems of wheat diploid ancestors. Synteny perturbations were characterized in 31 paralogous sets of loci with perturbed synteny. Both insertions and deletions of loci were detected and both preferentially occurred in high recombination regions of chromosomes. 相似文献