全文获取类型
收费全文 | 352篇 |
免费 | 16篇 |
出版年
2024年 | 1篇 |
2023年 | 3篇 |
2022年 | 8篇 |
2021年 | 21篇 |
2020年 | 5篇 |
2019年 | 6篇 |
2018年 | 12篇 |
2017年 | 8篇 |
2016年 | 18篇 |
2015年 | 16篇 |
2014年 | 14篇 |
2013年 | 53篇 |
2012年 | 31篇 |
2011年 | 24篇 |
2010年 | 20篇 |
2009年 | 13篇 |
2008年 | 15篇 |
2007年 | 11篇 |
2006年 | 14篇 |
2005年 | 15篇 |
2004年 | 16篇 |
2003年 | 7篇 |
2002年 | 13篇 |
2001年 | 1篇 |
2000年 | 1篇 |
1999年 | 1篇 |
1998年 | 1篇 |
1997年 | 1篇 |
1989年 | 1篇 |
1988年 | 1篇 |
1987年 | 5篇 |
1986年 | 3篇 |
1985年 | 1篇 |
1982年 | 1篇 |
1981年 | 1篇 |
1980年 | 1篇 |
1978年 | 1篇 |
1975年 | 2篇 |
1974年 | 1篇 |
1972年 | 1篇 |
排序方式: 共有368条查询结果,搜索用时 15 毫秒
311.
Alka Mahale Maha W. Othman Sami Al Shahwan Ibrahim Al Jadaan Ohood Owaydha Zahid Khan Deepak P. Edward 《PloS one》2015,10(4)
Purpose
Ahmed glaucoma valve (AGV) implant is an aqueous shunt device used to control intraocular pressure in glaucoma. Implant failure results from impervious encapsulation of the shunt plate causing increased hydraulic resistance and raised intraocular pressure. We hypothesized that deregulation of fibrosis pathway contributes to capsular resistance. We tested this by studying fibrosis related gene expression in failed AGV implants.Methods
Differential gene expression was examined in failed AGV capsules and compared to normal control tenon. Following total RNA extraction, 84 key genes in fibrosis pathway were examined by real-time PCR using RT2 Profiler PCR Array. Relative gene expression was calculated using ΔΔCt method. Gene specific TaqMan assays were used to validate select genes with ≥2 fold differential expression in the array expression profile.Results
We observed differential expression in several genes in the fibrosis pathway. Almost half (39/84) of examined genes showed ≥2 fold differential expression in majority of capsules examined on the array. TaqMan assays for select genes including CCN2 (CTGF), THBS1, SERPINE1, THBS2, COL3A1, MMP3, and IL1A in an increased validation sample set showed significant changes in expression (p value from <0.001 to 0.022) at a high frequency in concurrence with our array results.Conclusions
Pathway-focused analyses identified candidate genes with altered expression providing molecular evidence for deregulation of the fibrosis pathway in AGV failure. 相似文献312.
313.
314.
为研究淡水贝类NF-κB/Rel信号通路中核因子κB(Nuclear factor-κappaB, NF-κB)和NF-κB抑制因子(Inhibitors of NF-κB, IκB)的功能,对池蝶蚌(Hyriopsis schlegelii)IκBα和c-Rel(以下简称HsIκBα和Hsc-Rel)的序列结构、表达特征及Hs IκBα和Hsc-Rel之间的相互关系进行了分析。结果表明, Hs IκBα的c DNA全长为1783 bp,其开放阅读框(Open Reading Frame, ORF)为1083 bp,编码360个氨基酸。Hsc-Rel的cDNA为2414 bp, ORF为2298 bp,编码765个氨基酸。通过构建HsIκBα-ORF-GST和Hsc-Rel-RHD-HIS重组质粒、原核诱导表达和纯化,进行GST-pull down,通过SDS-PAGE和Western Blot检测研究,发现HsIκBα和Hsc-Rel-RHD存在直接的相互作用。通过对池蝶蚌进行脂多糖(Lipopolysaccharide, LPS)刺激后,分别在7个时间点(0、6h、12h、24h、... 相似文献
315.
316.
Vibrio cholerae produces a zinc-containing and calcium-stabilized soluble hemagglutinin/protease, which has been earlier shown to have the
ability to cleave several physiologically important substrates including mucin, fibronectin and lactoferin. This study presents
homology modeling of hemagglutinin/protease (vibriolysin) from Vibrio cholerae in the presence of inhibitor HPI [N-(1-carboxy-3-phenylpropyl)-phenylalanyl-alpha-aspargine]. The 3D structure was predicted based on its sequence homology with
Pseudomonas aeruginosa elastase (PAE). Comparison of the 3D structures of PAE and HA/P reveals a remarkable similarity having a conserved α + β
domain. The inhibitor shows similar binding features as seen in other metalloproteases of M4 peptidase family. The study also
highlights the key catalytic residues as well as the residues at the S1 and
binding sub-sites. The similarities between the two proteins provide support for the hypothesis that the two enzymes have
similar three-dimensional structures and a common mechanism of action. The fact that both enzymes are secreted as zinc-containing
proteases, led us to further hypothesize that they may play similar role in pathogenesis. 相似文献
317.
Liu J Lin TH Cole AG Wen R Zhao L Brescia MR Jacob B Hussain Z Appell KC Henderson I Webb ML 《FEBS letters》2008,582(5):785-791
Angiopoietins and Tie2 receptor were recently identified as an endothelial cell-specific ligand-receptor system that is critical for vascular development and postnatal pathologic angiogenesis by mediating vascular integrity. In this study, we identified a series of small-molecule Tie2 inhibitors, which blocked Ang1-induced Tie2 autophosphorylation and downstream signaling with an IC(50) value at 0.3 microM. Further optimization yields improved selectivity, aqueous solubility, microsomal stability and cytochrome P450 profile for one of the compounds (compound 7). Both compound 1 and compound 7 inhibit endothelial cell tube formation. Furthermore, in a rat model of Matrigel-induced choroidal neovascularization, compound 7 significantly diminished aberrant vessel growth. Our findings demonstrate a potential clinical benefit by specifically targeting Tie2-mediated angiogenic disorders. 相似文献
318.
CC2D2A, encoding a coiled-coil and C2 domain protein, causes autosomal-recessive mental retardation with retinitis pigmentosa 下载免费PDF全文
Noor A Windpassinger C Patel M Stachowiak B Mikhailov A Azam M Irfan M Siddiqui ZK Naeem F Paterson AD Lutfullah M Vincent JB Ayub M 《American journal of human genetics》2008,82(4):1011-1018
Autosomal-recessive inheritance is believed to be relatively common in mental retardation (MR), although only four genes for nonsyndromic autosomal-recessive mental retardation (ARMR) have been reported. In this study, we ascertained a consanguineous Pakistani family with ARMR in four living individuals from three branches of the family, plus an additional affected individual later identified as a phenocopy. Retinitis pigmentosa was present in affected individuals, but no other features suggestive of a syndromic form of MR were found. We used Affymetrix 500K microarrays to perform homozygosity mapping and identified a homozygous and haploidentical region of 11.2 Mb on chromosome 4p15.33-p15.2. Linkage analysis across this region produced a maximum two-point LOD score of 3.59. We sequenced genes within the critical region and identified a homozygous splice-site mutation segregating in the family, within a coiled-coil and C2 domain-containing gene, CC2D2A. This mutation leads to the skipping of exon 19, resulting in a frameshift and a truncated protein lacking the C2 domain. Conservation analysis for CC2D2A suggests a functional domain near the C terminus as well as the C2 domain. Preliminary functional studies of CC2D2A suggest a possible role in Ca(2+)-dependent signal transduction. Identifying the function of CC2D2A, and a possible common pathway with CC2D1A, in correct neuronal development and functioning may help identify possible therapeutic targets for MR. 相似文献
319.
A variety of evidence has been obtained that estrogens are weak tumor initiators. A major step in the multi-stage process leading to tumor initiation involves metabolic formation of 4-catechol estrogens from estradiol (E2) and/or estrone and further oxidation of the catechol estrogens to the corresponding catechol estrogen quinones. The electrophilic catechol quinones react with DNA mostly at the N-3 of adenine (Ade) and N-7 of guanine (Gua) by 1,4-Michael addition to form depurinating adducts. The N3Ade adducts depurinate instantaneously, whereas the N7Gua adducts depurinate with a half-life of several hours. Only the apurinic sites generated in the DNA by the rapidly depurinating N3Ade adducts appear to produce mutations by error-prone repair. Analogously to the catechol estrogen-3,4-quinones, the synthetic nonsteroidal estrogen hexestrol-3',4'-quinone (HES-3',4'-Q) reacts with DNA at the N-3 of Ade and N-7 of Gua to form depurinating adducts. We report here an additional similarity between the natural estrogen E2 and the synthetic estrogen HES, namely, the slow loss of deoxyribose from the N7deoxyguanosine (N7dG) adducts formed by reaction of E2-3,4-Q or HES-3',4'-Q with dG. The half-life of the loss of deoxyribose from the N7dG adducts to form the corresponding 4-OHE2-1-N7Gua and 3'-OH-HES-6'-N7Gua is 6 or 8 h, respectively. The slow cleavage of this glycosyl bond in DNA seems to limit the ability of these adducts to induce mutations. 相似文献
320.
Reseland JE Mundal HH Hollung K Haugen F Zahid N Anderssen SA Drevon CA 《Prostaglandins, leukotrienes, and essential fatty acids》2005,73(1):43-49
BACKGROUND: Leptin might influence body weight among smokers. DESIGN: (A) Screening of plasma leptin levels in 222 sedentary, smoking and non-smoking middle-aged men. (B) Double-blind, placebo-controlled smoking intervention on smokers (n=31). (C) Non-smokers (n=40) received chewing gum with nicotine (2mg nicotine, n=23) or without nicotine (n=19). (D) The effects of nicotine (0.05 and 0.5 microg/mL) were monitored on leptin secretion and mRNA levels in a human placental cell line (BeWo) expressing leptin, a murine adipocyte cell line (3T3-L1) and human adipose tissue explants. RESULTS: (A) Plasma leptin levels in smoking men (8.4+/-8.4 ng/mL, n=100) was lower as compared to non-smokers (10.3+/-7.3 ng/mL, n=122) (P<0.001), even when adjusted for differences in body mass index (BMI) (P<0.001). (B) A significant reduction (P=0.02) in plasma concentration of leptin was found already after smoking one cigarette. Concomitant with the 3-5 fold increase in plasma nicotine concentration after the first cigarette, we observed increased plasma adrenaline levels (P=0.005). (C) There was no effect of nicotine on plasma leptin levels in non-smokers receiving nicotine-containing chewing gum, and plasma concentrations of catecholamines were unaltered. (D) There was no effect of nicotine on leptin mRNA expression after incubation with cells or adipose tissue. CONCLUSION: Cigarette smoking reduced plasma leptin concentration in vivo, whereas nicotine had no direct effect on leptin expression in vitro. Nicotine might indirectly reduce leptin secretion via enhanced plasma catecholamine concentration. 相似文献