全文获取类型
收费全文 | 1699篇 |
免费 | 200篇 |
专业分类
1899篇 |
出版年
2022年 | 10篇 |
2021年 | 29篇 |
2020年 | 8篇 |
2019年 | 11篇 |
2018年 | 24篇 |
2017年 | 21篇 |
2016年 | 29篇 |
2015年 | 51篇 |
2014年 | 65篇 |
2013年 | 97篇 |
2012年 | 84篇 |
2011年 | 84篇 |
2010年 | 52篇 |
2009年 | 47篇 |
2008年 | 88篇 |
2007年 | 94篇 |
2006年 | 109篇 |
2005年 | 81篇 |
2004年 | 118篇 |
2003年 | 90篇 |
2002年 | 78篇 |
2001年 | 67篇 |
2000年 | 57篇 |
1999年 | 47篇 |
1998年 | 30篇 |
1997年 | 20篇 |
1996年 | 16篇 |
1995年 | 28篇 |
1994年 | 22篇 |
1993年 | 19篇 |
1992年 | 38篇 |
1991年 | 27篇 |
1990年 | 28篇 |
1989年 | 25篇 |
1988年 | 20篇 |
1987年 | 14篇 |
1986年 | 10篇 |
1985年 | 14篇 |
1984年 | 14篇 |
1983年 | 8篇 |
1982年 | 18篇 |
1981年 | 11篇 |
1980年 | 9篇 |
1979年 | 13篇 |
1978年 | 14篇 |
1977年 | 14篇 |
1974年 | 6篇 |
1972年 | 6篇 |
1971年 | 6篇 |
1969年 | 5篇 |
排序方式: 共有1899条查询结果,搜索用时 0 毫秒
51.
H. Matsuo T. Takada K. Ichida T. Nakamura A. Nakayama Y. Takada 《Nucleosides, nucleotides & nucleic acids》2013,32(12):1098-1104
The ATP-binding cassette, subfamily G, member 2 gene ABCG2/BCRP locates in a gout-susceptibility locus (MIM 138900) on chromosome 4q. Recent genome-wide association studies also showed that the ABCG2 gene relates to serum uric acid levels and gout. Since ABCG2 is also known as a transporter of nucleotide analogs that are structurally similar to urate, and is an exporter that has common polymorphic reduced functionality variants, ABCG2 could be a urate secretion transporter and a gene causing gout. To find candidate mutations in ABCG2, we performed a mutation analysis of the ABCG2 gene in 90 Japanese patients with hyperuricemia and found six non-synonymous mutations. Among the variants, ATP-dependent urate transport was reduced or eliminated in five variants, and two out of the five variants (Q126X and Q141K) were frequently detected in patients. Haplotype frequency analysis revealed that there is no simultaneous presence of Q126X and Q141K in one haplotype. As Q126X and Q141K are a nonfunctional and half-functional haplotype, respectively, their genotype combinations are divided into four estimated functional groups. The association study with 161 male gout patients and 865 male controls showed that all of those who had dysfunctional ABCG2 had an increased risk of gout, and that a remarkable risk was observed in those with ≤1/4 function (OR, 25.8; 95% CI, 10.3–64.6; p = 3.39 × 10?21). In 2,150 Japanese individuals, the frequency of those with dysfunctional ABCG2 was more than 50%. Our function-based clinicogenetic analysis identified the combinations of dysfunctional variants of ABCG2 as a major contributing factor in Japanese patients with gout. 相似文献
52.
Hirotaka Matsuo Tappei Takada Kimiyoshi Ichida Takahiro Nakamura Akiyoshi Nakayama Hiroshi Suzuki 《Nucleosides, nucleotides & nucleic acids》2013,32(12):1117-1128
Recent genome-wide association studies showed that serum uric acid (SUA) levels relate to ABCG2/BCRP gene, which locates in a gout-susceptibility locus revealed by a genome-wide linkage study. Together with the ABCG2 characteristics, we hypothesized that ABCG2 transports urate and its dysfunction causes hyperuricemia and gout. Transport assays showed ATP-dependent transport of urate via ABCG2. Kinetic analysis revealed that ABCG2 mediates high-capacity transport of urate (Km: 8.24 ± 1.44 mM) even under high-urate conditions. Mutation analysis of ABCG2 in 90 Japanese hyperuricemia patients detected six nonsynonymous mutations, including five dysfunctional variants. Two relatively frequent dysfunctional variants, Q126X and Q141K, were then examined. Quantitative trait locus analysis of 739 Japanese individuals showed that Q141K increased SUA as the number of minor alleles of Q141K increased (p = 6.60 × 10?5). Haplotype frequency analysis revealed that there is no simultaneous presence of Q126X and Q141K in one haplotype. Becuase Q126X and Q141K are assigned to nonfunctional and half-functional haplotypes, respectively, their genotype combinations are divided into four functional groups. The association study with 161 male gout patients and 865 male controls showed that all of those with dysfunctional ABCG2 increased the gout risk, especially those with ≤1/4 function (OR, 25.8; 95% CI, 10.3–64.6; p = 3.39 × 10?21). These genotypes were found in 10.1% of gout patients, but in only 0.9% of control. Our function-based clinicogenetic (FBCG) analysis showed that combinations of the two dysfunctional variants are major causes of gout, thereby providing a new approach for prevention and treatment of the gout high-risk population. 相似文献
53.
Takashi Sakudoh Tetsuya Iizuka Junko Narukawa Hideki Sezutsu Isao Kobayashi Seigo Kuwazaki Yutaka Banno Akitoshi Kitamura Hiromu Sugiyama Naoko Takada Hirofumi Fujimoto Keiko Kadono-Okuda Kazuei Mita Toshiki Tamura Kimiko Yamamoto Kozo Tsuchida 《The Journal of biological chemistry》2010,285(10):7739-7751
The transport pathway of specific dietary carotenoids from the midgut lumen to the silk gland in the silkworm, Bombyx mori, is a model system for selective carotenoid transport because several genetic mutants with defects in parts of this pathway have been identified that manifest altered cocoon pigmentation. In the wild-type silkworm, which has both genes, Yellow blood (Y) and Yellow cocoon (C), lutein is transferred selectively from the hemolymph lipoprotein to the silk gland cells where it is accumulated into the cocoon. The Y gene encodes an intracellular carotenoid-binding protein (CBP) containing a lipid-binding domain known as the steroidogenic acute regulatory protein-related lipid transfer domain. Positional cloning and transgenic rescue experiments revealed that the C gene encodes Cameo2, a transmembrane protein gene belonging to the CD36 family genes, some of which, such as the mammalian SR-BI and the fruit fly ninaD, are reported as lipoprotein receptors or implicated in carotenoid transport for visual system. In C mutant larvae, Cameo2 expression was strongly repressed in the silk gland in a specific manner, resulting in colorless silk glands and white cocoons. The developmental profile of Cameo2 expression, CBP expression, and lutein pigmentation in the silk gland of the yellow cocoon strain were correlated. We hypothesize that selective delivery of lutein to specific tissue requires the combination of two components: 1) CBP as a carotenoid transporter in cytosol and 2) Cameo2 as a transmembrane receptor on the surface of the cells. 相似文献
54.
Junya Nojima Kazuhiro Kanomata Yumi Takada Toru Fukuda Shoichiro Kokabu Satoshi Ohte Takatora Takada Tohru Tsukui Takamasa S. Yamamoto Hiroki Sasanuma Katsumi Yoneyama Naoto Ueno Yasushi Okazaki Ryutaro Kamijo Tetsuya Yoda Takenobu Katagiri 《The Journal of biological chemistry》2010,285(20):15577-15586
55.
Lin SP Coan P da Rocha ST Seitz H Cavaille J Teng PW Takada S Ferguson-Smith AC 《Development (Cambridge, England)》2007,134(2):417-426
Genomic imprinting is an epigenetic mechanism controlling parental-origin-specific gene expression. Perturbing the parental origin of the distal portion of mouse chromosome 12 causes alterations in the dosage of imprinted genes resulting in embryonic lethality and developmental abnormalities of both embryo and placenta. A 1 Mb imprinted domain identified on distal chromosome 12 contains three paternally expressed protein-coding genes and multiple non-coding RNA genes, including snoRNAs and microRNAs, expressed from the maternally inherited chromosome. An intergenic, parental-origin-specific differentially methylated region, the IG-DMR, which is unmethylated on the maternally inherited chromosome, is necessary for the repression of the paternally expressed protein-coding genes and for activation of the maternally expressed non-coding RNAs: its absence causes the maternal chromosome to behave like the paternally inherited one. Here, we characterise the developmental consequences of this epigenotype switch and compare these with phenotypes associated with paternal uniparental disomy of mouse chromosome 12. The results show that the embryonic defects described for uniparental disomy embryos can be attributed to this one cluster of imprinted genes on distal chromosome 12 and that these defects alone, and not the mutant placenta, can cause prenatal lethality. In the placenta, the absence of the IG-DMR has no phenotypic consequence. Loss of repression of the protein-coding genes occurs but the non-coding RNAs are not repressed on the maternally inherited chromosome. This indicates that the mechanism of action of the IG-DMR is different in the embryo and the placenta and suggests that the epigenetic control of imprinting differs in these two lineages. 相似文献
56.
YH Chang CP Lee MT Su JT Wang JY Chen SF Lin CH Tsai MJ Hsieh K Takada MR Chen 《PloS one》2012,7(6):e39217
Epstein-Barr virus (EBV) induces an uncoordinated S-phase-like cellular environment coupled with multiple prophase-like events in cells replicating the virus. The EBV encoded Ser/Thr kinase BGLF4 has been shown to induce premature chromosome condensation through activation of condensin and topoisomerase II and reorganization of the nuclear lamina to facilitate the nuclear egress of nucleocapsids in a pathway mimicking Cdk1. However, the observation that RB is hyperphosphorylated in the presence of BGLF4 raised the possibility that BGLF4 may have a Cdk2-like activity to promote S-phase progression. Here, we investigated the regulatory effects of BGLF4 on cell cycle progression and found that S-phase progression and DNA synthesis were interrupted by BGLF4 in mammalian cells. Expression of BGLF4 did not compensate Cdk1 defects for DNA replication in S. cerevisiae. Using time-lapse microscopy, we found the fate of individual HeLa cells was determined by the expression level of BGLF4. In addition to slight cell growth retardation, BGLF4 elicits abnormal chromosomal structure and micronucleus formation in 293 and NCP-TW01 cells. In Saos-2 cells, BGLF4 induced the hyperphosphorylation of co-transfected RB, while E2F1 was not released from RB-E2F1 complexes. The E2F1 regulated activities of the cyclin D1 and ZBRK1 promoters were suppressed by BGLF4 in a dose dependent manner. Detection with phosphoamino acid specific antibodies revealed that, in addition to Ser780, phosphorylation of the DNA damage-responsive Ser612 on RB was enhanced by BGLF4. Taken together, our study indicates that BGLF4 may directly or indirectly induce a DNA damage signal that eventually interferes with host DNA synthesis and delays S-phase progression. 相似文献
57.
58.
A 3-Mb Sequence-Ready Contig Map Encompassing the Multiple Disease Gene Cluster on Chromosome 11q13.1-q13.3 总被引:1,自引:0,他引:1
Kitamura Eiko; Hosoda Fumie; Fukushima Michiyo; Asakawa Shuichi; Shimizu Nobuyoshi; Imai Takashi; Soeda Eiichi; Ohki Misao 《DNA research》1997,4(4):281-289
Despite the presence of several human disease genes on chromosome11q13, few of them have been molecularly cloned. Here, we reportthe construction of a contig map encompassing 11q13.1q13.3using bacteriophage P1 (P1), bacterial artificial chromosome(BAC), and P1-derived artificial chromosome (PAC). The contigmap comprises 32 P1 clones, 27 BAC clones, 6 PAC clones, and1 YAC clone and spans a 3-Mb region from D11S480 to D11S913.The map encompasses all the candidate loci of Bardet-Biedlesyndrome type I (BBS1) and spinocerebellar ataxia type 5 (SCA5),one-third of the distal region for hereditary paraganglioma2 (PGL2), and one-third of the central region for insulin-dependentdiabetes mellitus 4 (IDDM4). In the process of map construction,61 new sequence-tagged site (STS) markers were developed fromthe Not I linking clones and the termini of clone inserts. Wehave also mapped 30 ESTs on this map. This contig map will facilitatethe isolation of polymorphic markers for a more re.ned analysisof the disease gene region and identi.cation of candidate genesby direct cDNA selection, as well as prediction of gene functionfrom sequence information of these bacterial clones. 相似文献
59.
David W. Frederick James G. Davis Antonio Dávila Jr. Beamon Agarwal Shaday Michan Michelle A. Puchowicz Eiko Nakamaru-Ogiso Joseph A. Baur 《The Journal of biological chemistry》2015,290(3):1546-1558
The NAD biosynthetic precursors nicotinamide mononucleotide and nicotinamide riboside are reported to confer resistance to metabolic defects induced by high fat feeding in part by promoting oxidative metabolism in skeletal muscle. Similar effects are obtained by germ line deletion of major NAD-consuming enzymes, suggesting that the bioavailability of NAD is limiting for maximal oxidative capacity. However, because of their systemic nature, the degree to which these interventions exert cell- or tissue-autonomous effects is unclear. Here, we report a tissue-specific approach to increase NAD biosynthesis only in muscle by overexpressing nicotinamide phosphoribosyltransferase, the rate-limiting enzyme in the salvage pathway that converts nicotinamide to NAD (mNAMPT mice). These mice display a ∼50% increase in skeletal muscle NAD levels, comparable with the effects of dietary NAD precursors, exercise regimens, or loss of poly(ADP-ribose) polymerases yet surprisingly do not exhibit changes in muscle mitochondrial biogenesis or mitochondrial function and are equally susceptible to the metabolic consequences of high fat feeding. We further report that chronic elevation of muscle NAD in vivo does not perturb the NAD/NADH redox ratio. These studies reveal for the first time the metabolic effects of tissue-specific increases in NAD synthesis and suggest that critical sites of action for supplemental NAD precursors reside outside of the heart and skeletal muscle. 相似文献
60.
Eiko Matsumura Eiko Yamamoto Atsushi Numata Tatsu Kawano Takashi Shin Sawao Murao 《Bioscience, biotechnology, and biochemistry》2013,77(5):1355-1357
Esters selected from the combination of tricycloalkanecarboxylic acids and some representative pyrethroidal alcohols were prepared, and their insecticidal activities were measured by topical application on housefly, mosquito and German cockroach. Both the exo- and endo-isomers of 2,3-trimethylenenorbornane-2-carboxylic acid exhibited a high level of activity when esterified with m-phenoxymandelonitrile. Piperonyl butoxide showed a strong synergistic effect on some of the esters. Several structural resemblances were found among these active tricyclic acids and the chrysanthemummonocarboxylic acids, which were suggested to be related to insecticidal activity. 相似文献