全文获取类型
收费全文 | 1343篇 |
免费 | 60篇 |
国内免费 | 3篇 |
出版年
2023年 | 4篇 |
2022年 | 5篇 |
2021年 | 13篇 |
2020年 | 4篇 |
2019年 | 16篇 |
2018年 | 22篇 |
2017年 | 19篇 |
2016年 | 31篇 |
2015年 | 32篇 |
2014年 | 51篇 |
2013年 | 69篇 |
2012年 | 95篇 |
2011年 | 94篇 |
2010年 | 52篇 |
2009年 | 74篇 |
2008年 | 93篇 |
2007年 | 95篇 |
2006年 | 77篇 |
2005年 | 95篇 |
2004年 | 81篇 |
2003年 | 88篇 |
2002年 | 76篇 |
2001年 | 18篇 |
2000年 | 17篇 |
1999年 | 11篇 |
1998年 | 18篇 |
1997年 | 15篇 |
1996年 | 6篇 |
1995年 | 8篇 |
1994年 | 9篇 |
1993年 | 10篇 |
1992年 | 13篇 |
1991年 | 12篇 |
1990年 | 10篇 |
1989年 | 8篇 |
1988年 | 5篇 |
1987年 | 5篇 |
1986年 | 6篇 |
1985年 | 5篇 |
1984年 | 1篇 |
1983年 | 9篇 |
1982年 | 5篇 |
1981年 | 4篇 |
1980年 | 4篇 |
1979年 | 7篇 |
1978年 | 5篇 |
1977年 | 2篇 |
1976年 | 2篇 |
1975年 | 3篇 |
1973年 | 2篇 |
排序方式: 共有1406条查询结果,搜索用时 546 毫秒
71.
Preferential paternal origin of microdeletions caused by prezygotic chromosome or chromatid rearrangements in Sotos syndrome 总被引:3,自引:0,他引:3
下载免费PDF全文
![点击此处可从《American journal of human genetics》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Miyake N Kurotaki N Sugawara H Shimokawa O Harada N Kondoh T Tsukahara M Ishikiriyama S Sonoda T Miyoshi Y Sakazume S Fukushima Y Ohashi H Nagai T Kawame H Kurosawa K Touyama M Shiihara T Okamoto N Nishimoto J Yoshiura K Ohta T Kishino T Niikawa N Matsumoto N 《American journal of human genetics》2003,72(5):1331-1337
Sotos syndrome (SoS) is characterized by pre- and postnatal overgrowth with advanced bone age; a dysmorphic face with macrocephaly and pointed chin; large hands and feet; mental retardation; and possible susceptibility to tumors. It has been shown that the major cause of SoS is haploinsufficiency of the NSD1 gene at 5q35, because the majority of patients had either a common microdeletion including NSD1 or a truncated type of point mutation in NSD1. In the present study, we traced the parental origin of the microdeletions in 26 patients with SoS by the use of 16 microsatellite markers at or flanking the commonly deleted region. Deletions in 18 of the 20 informative cases occurred in the paternally derived chromosome 5, whereas those in the maternally derived chromosome were found in only two cases. Haplotyping analysis of the marker loci revealed that the paternal deletion in five of seven informative cases and the maternal deletion in one case arose through an intrachromosomal rearrangement, and two other cases of the paternal deletion involved an interchromosomal event, suggesting that the common microdeletion observed in SoS did not occur through a uniform mechanism but preferentially arose prezygotically. 相似文献
72.
Taketani Y Nomoto M Yamamoto H Isshiki M Morita K Arai H Miyamoto K Kato S Takeda E 《Biochemical and biophysical research communications》2003,305(2):287-291
The mechanisms by which Pi depletion rapidly regulates gene expression and cellular function have not been clarified. Here, we found a rapid increase in intracellular ionized calcium [Ca(2+)](i) by phosphate depletion in LLC-PK(1) cells using confocal microscopy with the green-fluorescence protein based calcium indicator "yellow cameleon 2.1." The increase of [Ca(2+)](i) was observed in the presence or absence of extracellular Ca(2+). At the same time, an approximately twofold increase in intracellular inositol 1,4,5-triphosphate (IP(3)) occurred in response to the acute Pi depletion in the medium. Furthermore, 2-aminoethoxydiphenyl borate completely blocked the [Ca(2+)](i) increase induced by Pi depletion. These results suggest that Pi depletion causes IP(3)-mediated release of Ca(2+) from intracellular Ca(2+) pools and rapidly increases [Ca(2+)](i) in LLC-PK(1) cells. 相似文献
73.
Sun D Ono K Okajima T Tanizawa K Uchida M Yamamoto Y Mathews FS Davidson VL 《Biochemistry》2003,42(37):10896-10903
Quinohemoprotein amine dehydrogenase (QHNDH) possesses a cysteine tryptophylquinone (CTQ) prosthetic group that catalyzes the oxidative deamination of primary amines. In addition to CTQ, two heme c cofactors are present in QHNDH that mediate the transfer of the substrate-derived electrons from CTQ to an external electron acceptor. Steady-state kinetic assays yielded relatively small k(cat) values (<6 s(-1)), and the rate-limiting step appears to be the interprotein electron transfer from heme in QHNDH to the external electron acceptor. Transient kinetic studies of the CTQ-dependent reduction of heme in QHNDH by amine substrates yielded different rate constants for different substrates (72, 190, and 162 s(-1) for methylamine, butylamine, and benzylamine, respectively). Deuterium kinetic isotope effect (KIE) values of 5.3, 3.9, and 8.5 were observed, respectively, for the reactions of methylamine, butylamine, and benzylamine. These results suggest that the abstraction of a proton from the alpha-methylene group of the substrate, which occurs concomitant with CTQ reduction, is the rate-limiting step in the CTQ-dependent reduction of hemes in QHNDH by these amine substrates. In contrast, the reaction of 2-phenylethylamine with QHNDH does not exhibit a significant KIE ((H)k(3)/(D)k(3) = 1.05) and exhibits a much smaller rate constant of 16 s(-1). This suggests that for 2-phenylethylamine, the rate-limiting step in the single-turnover reaction is either hydrolysis of the imine reaction intermediate from CTQ or product release prior to intraprotein electron transfer. Analysis of the products of the reactions of QHNDH with chiral deuterated 2-phenylethylamines demonstrated that the enzyme abstracts the pro-S proton of the substrate in a highly stereospecific manner. Inspection of the crystal structure of phenylhydrazine-inhibited QHNDH suggests that Asp33(gamma) is the residue that performs the proton abstraction. On the basis of these results, kinetic and chemical reaction mechanisms for QHNDH are proposed and discussed in the context of the crystal structure of the enzyme. 相似文献
74.
Aminopeptidase A is a zinc metalloenzyme that generates brain angiotensin III, which exerts a tonic stimulatory action on blood pressure in hypertensive animals. We have previously constructed a three-dimensional model of the ectodomain of this enzyme, using the crystal structure of leukotriene A4 hydrolase/aminopeptidase as a template. According to this model, Glu-215, which is located in the active site, hydrogen bonds to the amino moiety of the inhibitor, 4-amino-4-phosphonobutyric acid (GluPhos), a phosphonic acid anologue of glutamic acid. Replacement of this residue with an aspartate or an alanine in the model abolished this interaction and led to a change in the position of the inhibitor in the active site. Mutagenic replacement of Glu-215 with an aspartate or an alanine drastically reduced the affinity of the recombinant enzymes for the substrate by a factor of 10 or 17, respectively, and the rate of hydrolysis by a factor of 14 or 6, respectively. Two isomers of GluPhos with different N-terminal amine positions differed considerably in their ability to inhibit the wild type (by a factor of 40), but not the mutated enzymes. These results, together with the interaction predicted by the model, demonstrate that Glu-215 interacts with the N-terminal amine of the substrate, thereby contributing, together with Glu-352, to the determination of the exopeptidase specificity of aminopeptidase A. 相似文献
75.
76.
Laminin-alpha5 chain was localized in all epithelial basement membranes (BMs) of mouse submandibular gland (SMG) from the onset of branching morphogenesis and became restricted to BMs of epithelial ducts in the adult. To investigate whether the laminin-alpha5 chain plays a role in branching morphogenesis, a set of cell-adhesive peptides from the C-terminal globular domains (LG1-5) was tested for their effects in SMG organ cultures. One peptide, LVLFLNHGH (A5G77f), which represents a sequence located in the connecting loop between strands E and F of LG4, perturbed branching morphogenesis and resulted in irregularities in the contours of epithelial structures, with formation of deep clefts. The data suggest a role for the laminin-alpha5 LG4 module in the development of the duct system, rather than in the bifurcation of epithelial clusters. The epithelial BM of A5G77f-peptide-treated explants was continuous, which was in contrast to our previous finding of impaired epithelial BM assembly in explants treated with the laminin-alpha1 LG4 module peptide, or with a monoclonal antibody against this domain. A5G77f also perturbed in vitro development of lung and kidney. These results suggest a crucial role for the LG4 module of laminin-alpha5 in epithelial morphogenesis that is distinct from that of the laminin-alpha1 LG4. 相似文献
77.
78.
Satoh W Nakata M Yamamoto H Ezaki T Hiramatsu K 《Applied and environmental microbiology》2002,68(12):6466-6470
Oligonucleotide probes and colony hybridization (CH) were applied to enumerate organisms of the genus Legionella in cooling tower water. The CH counts indicated almost the same results as CFU counts in cultivated samples derived from the water. It was concluded that it is possible to substitute the CH procedure for the conventional one. 相似文献
79.
Cyotomedical therapy for insulinopenic diabetes using microencapsulated pancreatic beta cell lines 总被引:3,自引:0,他引:3
Suzuki R Okada N Miyamoto H Yoshioka T Sakamoto K Oka H Tsutsumi Y Nakagawa S Miyazaki J Mayumi T 《Life sciences》2002,71(15):1717-1729
Current therapy for type 1 diabetes mellitus involves a daily regimen of multiple subcutaneous or intramuscular injections of recombinant human insulin. To achieve long-term insulin delivery in vivo, we investigated the applicability of cytomedical therapy using beta TC6 cells or MIN6 cells, both of which are murine pancreatic beta cell lines that secrete insulin in a subphysiologically or physiologically regulated manner, respectively. We examined this therapy in the insulinopenic diabetic mice intraperitoneally injected with beta TC6 cells or MIN6 cells microencapsulated within alginate-poly(L)lysine-alginate membranes (APA-beta TC6 cells or APA-MIN6 cells). The diabetic mice treated with APA-beta TC6 cells fell into hypoglycemia, whereas those injected with APA-MIN6 cells maintained normal blood glucose concentrations for over 2 months without developing hypoglycemia. In addition, we also conducted an oral glucose tolerance test using these mice. The blood glucose concentrations of normal and of diabetic mice injected with APA-MIN6 cells similarly changed over time, although the blood insulin concentration increased later in the injected diabetic mice than in the former. These results suggest that cytomedicine utilizing microencapsulated pancreatic beta cell lines with a physiological glucose sensor may be a beneficial and safe therapy with which to treat diabetes mellitus. 相似文献
80.
Characterization of mouse cysteinyl leukotriene receptors mCysLT1 and mCysLT2: differential pharmacological properties and tissue distribution 总被引:1,自引:0,他引:1
Ogasawara H Ishii S Yokomizo T Kakinuma T Komine M Tamaki K Shimizu T Izumi T 《The Journal of biological chemistry》2002,277(21):18763-18768
Cysteinyl leukotrienes (LTs) are important proinflammatory mediators. Their precise roles in mice need to be elucidated to interpret mouse models of inflammatory diseases. For this purpose, we cloned and characterized mouse receptors for cysteinyl LTs, mCysLT(1) and mCysLT(2). mCysLT(1) and mCysLT(2) were composed of 339 amino acids with 87.3% identity and 309 amino acids with 73.4% identity to human orthologues, respectively. A pharmacological difference was noted between mouse and human CysLT(2). Pranlukast, a specific inhibitor for human CysLT(1), antagonized mCysLT(2) responses as determined by Ca(2+) elevation and receptor-induced promoter activation. The mRNA expressions of both mCysLTs were higher in C57BL/6 mice than in 129 mice. mCysLT(1) mRNA was expressed mainly in skin, lung, and small intestine. mCysLT(2) was seen more ubiquitously with high expressions in spleen, lung, and small intestine. By in situ hybridization we demonstrated for the first time that mCysLT(1) and mCysLT(2) were expressed in subcutaneous fibroblasts. The different pharmacological characteristics of CysLT(2) between human and mouse and the different distributions of CysLTs between mouse strains suggest that careful choice and interpretation are necessary for a study of CysLTs using animal models. 相似文献