全文获取类型
收费全文 | 2391篇 |
免费 | 302篇 |
国内免费 | 84篇 |
专业分类
耳鼻咽喉 | 7篇 |
儿科学 | 25篇 |
妇产科学 | 17篇 |
基础医学 | 519篇 |
口腔科学 | 43篇 |
临床医学 | 102篇 |
内科学 | 475篇 |
皮肤病学 | 43篇 |
神经病学 | 179篇 |
特种医学 | 19篇 |
外国民族医学 | 1篇 |
外科学 | 112篇 |
综合类 | 207篇 |
现状与发展 | 1篇 |
预防医学 | 50篇 |
眼科学 | 24篇 |
药学 | 456篇 |
中国医学 | 28篇 |
肿瘤学 | 469篇 |
出版年
2024年 | 7篇 |
2023年 | 55篇 |
2022年 | 67篇 |
2021年 | 119篇 |
2020年 | 108篇 |
2019年 | 105篇 |
2018年 | 85篇 |
2017年 | 103篇 |
2016年 | 122篇 |
2015年 | 179篇 |
2014年 | 195篇 |
2013年 | 267篇 |
2012年 | 181篇 |
2011年 | 225篇 |
2010年 | 171篇 |
2009年 | 148篇 |
2008年 | 134篇 |
2007年 | 104篇 |
2006年 | 83篇 |
2005年 | 76篇 |
2004年 | 55篇 |
2003年 | 36篇 |
2002年 | 19篇 |
2001年 | 15篇 |
2000年 | 13篇 |
1999年 | 9篇 |
1998年 | 9篇 |
1997年 | 3篇 |
1996年 | 9篇 |
1995年 | 3篇 |
1994年 | 3篇 |
1993年 | 5篇 |
1992年 | 5篇 |
1991年 | 7篇 |
1990年 | 3篇 |
1989年 | 5篇 |
1988年 | 1篇 |
1987年 | 3篇 |
1986年 | 3篇 |
1985年 | 5篇 |
1984年 | 6篇 |
1983年 | 4篇 |
1982年 | 2篇 |
1981年 | 5篇 |
1980年 | 1篇 |
1979年 | 1篇 |
1978年 | 5篇 |
1977年 | 2篇 |
1976年 | 5篇 |
1975年 | 1篇 |
排序方式: 共有2777条查询结果,搜索用时 484 毫秒
21.
Covalent modifications of histones integrate intracellular and extracellular cues to regulate the genome. H3 Lys 9 methylation (H3K9me) can direct heterochromatin formation and DNA methylation, while phosphorylation of H3 Ser 10 (H3S10p) drives gene activation and chromosome condensation. To examine the relationship between H3S10p, H3K9me, and DNA methylation in Neurospora crassa, we built and tested mutants of the putative H3S10 phosphatase, PP1. A PP1-impaired mutant showed increased H3S10p and selective reduction of methylation of H3K9 and DNA. Similarly, amino acid substitutions of H3S10 abolished methylation of H3K9 and DNA. Thus, H3S10 dephosphorylation by PP1 is required for DNA methylation of some loci. 相似文献
22.
23.
24.
We have established the content and molecular species of immunoreactive β-endorphin (ir-β-END) and immunoreactive N-acetyl-endorphin (ir-Nac-END) in rat neurointermediate lobe by specific radioimmunoassay (RIA) and high-performance liquid chromatography after chronic administration of dopamine (DA) agonists and antagonists. The DA agonist, bromocriptine, reduces tissue levels of all major immunoreactive species, in particular the C-terminally shortened N-acetylated forms. The DA antagonist, haloperidol, proportionally increases all immunoreactive forms, except Nac-β-END1–27, thus altering the relative abundance of this species. These data indicate that DA is involved in the control of both tissue levels and processing of β-END-like peptides in the rat neurointermediate lobe. 相似文献
25.
Histone deacetylase activity is necessary for chromosome condensation during meiotic maturation in Xenopus laevis 总被引:1,自引:0,他引:1
Chromosome condensation is thought to be an essential step for the faithful transmission of genetic information during cellular
division or gamete formation. The folding of DNA into metaphase chromosomes and its partition during the cell cycle remains
a fundamental cellular process that, at the molecular level, is poorly understood. Particularly, the role of histone deacetylase
(HDAC) activities in establishing and maintaining meiotic metaphase chromosome condensation has been little documented. In
order to better understand how metaphase chromosome condensation is achieved during meiosis, we explored, in vivo, the consequences of HDAC activities inhibition in a Xenopus oocyte model. Our results show that deacetylase activity plays a crucial role in chromosome condensation. This activity is
necessary for correct chromosome condensation since the earlier stages of meiosis, but dispensable for meiosis progression,
meiosis exit and mitosis entry. We show that HDAC activity correlates with chromosome condensation, being higher when chromosomes
are fully condensed and lower during interphase, when chromosomes are decondensed. In addition, we show that, unlike histone
H4, Xenopus maternal histone H3 is stored in the oocyte as a hypoacetylated form and is rapidly acetylated when the oocyte exits meiosis. 相似文献
26.
Precipitation of fibrinogen, fibrinogen degradation products and fibrin monomer by histone H3 总被引:1,自引:0,他引:1
Incubation of histone H3 with normal citrated plasma resulted in the formation of insoluble aggregates, as determined by turbidity measurements. The precipitate was subjected to sodium dodecyl sulfate polyacrylamide gel electrophoresis, confirming that fibrinogen was a major component. Purified fibrinogen precipitated rapidly as determined with turbidity experiments and experiments with radioiodinated protein. The amount of fibrinogen precipitation was strongly dependent on H3 concentration. Variation of ionic strength (0.2-0.84) and pH (5.3-7.4), however, had little or no effect on the reaction. Fibrinogen subjected to gelatin-Sepharose chromatography or dialysis against 3.3M urea reacted equivalently with H3. Precipitation of 125I-fibrinogen by H3 was strongly favored by increasing temperature (4 degrees-45 degrees C). Precipitation of fibrinogen by protamine was maximized by decreasing the temperature. In addition, formation of insoluble fibrinogen-protamine aggregates was highly dependent on ionic strength and pH, suggesting that different types of protein-interaction are involved in the two studied precipitation reactions. Of the fibrinogen degradation products, only fragment X precipitated significantly when incubated with H3. Radioiodinated fibrin monomer also precipitated when incubated with H3 in solutions of sufficient ionic strength to prevent spontaneous polymerization. The extent of precipitation was equivalent for fibrin monomer and fibrinogen. Fragment D inhibited the precipitation of fibrinogen by H3 or protamine. These studies indicate that the proteins termed "paracoagulants" are not all equivalent and that the hydrophobic domain of H3 plays a critical role in fibrinogen precipitation. 相似文献
27.
Huan Cai Yu Jiang Sheng Zhang Ning-Ning Cai Wen-Qian Zhu Rui Yang Bo Tang Zi-Yi Li Xue-Ming Zhang 《Andrologia》2021,53(6):e14056
Germplasm cryopreservation and expansion of gonocytes/prospermatogonia or spermatogonial stem cells (SSCs) are important; however, it's difficult in cattle. Since inhibitors of Mek1/2 and Gsk3β (2i) can enhance pluripotency maintenance, effects of 2i-based medium on the cultivation of bovine prospermatogonia from the cryopreserved tissues were examined. The testicular tissues of newborn bulls were well cryopreserved. High mRNA levels of prospermatogonium/SSC markers (PLZF, GFRα-1) and pluripotency markers (Oct4/Pouf5, Sox2, Nanog) were detected and the PLZF+/GFRα-1+ prospermatogonia were consistently identified immunohistochemically in the seminiferous cords. Using differential plating and Percoll-based centrifugation, 41.59% prospermatogonia were enriched and they proliferated robustly in 2i medium. The 2i medium boosted mRNA abundances of Pouf5, Sox2, Nanog, GFRα-1, PLZF, anti-apoptosis gene Bcl2, LIF receptor gene LIFR and enhanced PLZF protein expression, but suppressed mRNA expressions of spermatogonial differentiation marker c-kit and pro-apoptotic gene Bax, in the cultured prospermatogonia. It also alleviated H2O2-induced apoptosis of the enriched cells and decreased histone H3 lysine (K9) trimethylation (H3K9me3) and its methylase Suv39h1/2 mRNA level in the cultured seminiferous cords. Overall, 2i medium improves the cultivation of bovine prospermatogonia isolated from the cryopreserved testes, by inhibiting Suv39h1/2-mediated H3K9me3 through Mek1/2 and Gsk3β signalling, evidencing successful cryopreservation and expansion of bovine germplasm. 相似文献
28.
目的:探讨组蛋白脱乙酰化酶抑制剂FK228在红细胞生成素(EPO)介导的人红系前体细胞增殖与分化中的调节作用。方法:从经粒细胞集落刺激因子动员的肿瘤患者外周血单核细胞中分离CD34 细胞,用含干细胞生长因子(SCF)、EPO或SCF IL-3及不同浓度FK228的无血清培养基培养7d,分别用抗GPA及抗CD36单克隆抗体(mAb)染色并行流式细胞术检测;将CD34 细胞用含SCF IL-3的无血清培养基培养7d,分离CD36 GPA-细胞,将细胞用含有EPO FK228的无血清培养基培养7d,并行细胞计数;将CD36 GPAlow/-细胞用含EPO加或不加FK228的无血清培养基培养,并进行annexin V和PI染色。结果:FK228以一种剂量依赖方式抑制CD36 GPAhigh、CD36 GPAlow和CD36 GPA-细胞的产生;FK228可诱导CD36 GPAhigh和CD36 GPAlow/-细胞在含EPO的培养基中发生细胞凋亡。结论:FK228可抑制EPO介导的人红系前体细胞的增殖与分化。 相似文献
29.
F. Andreasen L. Elsborg S. Husted O. Thomsen 《European journal of clinical pharmacology》1978,14(1):57-67
Summary Sulfadiazine (SDZ) 800 mg and trimethoprim (TMP) 160 mg were given orally to 10 normal subjects and the concentration of SDZ and TMP in serum and urine was followed for 24 h. Both drugs showed a significant negative correlation between individual peak concentrations in serum and the body weight of the subject. Twelve hours after dosing the serum concentration was 12 to 25 µg/ml for SDZ and 0.3 to 1.1 µg/ml for TMP. Individual concentration ratios between SDZ and TMP in serum were 4.8 (1 h) – 145 (24 h), and in the urine the ratio was close to 6 throughout the 24 h collection period. The range of urinary concentrations was from 65 to 400 µg/ml for SDZ and from 13.8 to 93.4 µg/ml for TMP. The fraction acetylated SDZ/acetylated SDZ + SDZ was 21% during the 0–8 h period, 33% during the 8–15 h period and 41% during the 15–24 period. The average values for the notional volume of distribution, Vd, were 0.36±0.13 1/kg for SDZ and 1.39±0.25 1/kg for TMP. The average t1/2 was 15.2±7.4 h for SDZ and 7.4±1.9 h for TMP. Individual subjects showed a significant correlation between the serum clearance of TMP and SDZ (p<0.01) and also between the renal clearance of the two drugs (p<0.05). The serum clearance was significantly correlated with the renal clearance for TMP but not for SDZ. For SDZ Vd was significantly negatively correlated with the elimination constant; for TMP no such correlation was found. The serum clearance of SDZ was significantly correlated with the percentage of SDZ which was excreted as the (presumably) acetylated compound. The renal clearance of SDZ was independent of the serum concentration of SDZ. There was a highly significant negative correlation between the renal clearance and serum concentration of TMP, as well as for acetylated SDZ. The renal clearance of acetylated SDZ averaged more than six times that of unconjugated SDZ. With increased urine flow the renal clearances of TMP and SDZ were significantly increased. 相似文献
30.
目的:研究组蛋白去乙酰化酶抑制剂曲古抑菌素A(trichostatinA,TSA)对前列腺癌细胞的抑制作用机理。方法:四甲基偶唑氮蓝(MTT)检测药物对肿瘤细胞增殖的影响;Hochest33342染色观察细胞凋亡的形态学变化;Western印迹分析雄激素受体(AR)蛋白的表达;反转录PCR检测AR转录水平的变化。结果:TSA在较低浓度即能有效抑制LNCaP细胞的增殖,EC50为125.9nmol·L-1,并诱导肿瘤细胞凋亡;药物处理后细胞周期依赖性蛋白激酶抑制剂p21表达增高,AR呈时间及剂量依赖性被清除。TSA对AR的清除是发生在蛋白水平的降解,而不影响其转录。结论:TSA能够清除对细胞生长具有重要作用的AR细胞信号通路,从而对前列腺癌LNCaP细胞发挥抑制作用。 相似文献