全文获取类型
收费全文 | 1379篇 |
免费 | 67篇 |
出版年
2023年 | 2篇 |
2022年 | 6篇 |
2021年 | 11篇 |
2020年 | 10篇 |
2019年 | 4篇 |
2018年 | 21篇 |
2017年 | 12篇 |
2016年 | 20篇 |
2015年 | 32篇 |
2014年 | 40篇 |
2013年 | 85篇 |
2012年 | 55篇 |
2011年 | 77篇 |
2010年 | 51篇 |
2009年 | 52篇 |
2008年 | 97篇 |
2007年 | 87篇 |
2006年 | 93篇 |
2005年 | 96篇 |
2004年 | 100篇 |
2003年 | 91篇 |
2002年 | 101篇 |
2001年 | 9篇 |
2000年 | 13篇 |
1999年 | 18篇 |
1998年 | 20篇 |
1997年 | 18篇 |
1996年 | 20篇 |
1995年 | 21篇 |
1994年 | 34篇 |
1993年 | 21篇 |
1992年 | 13篇 |
1991年 | 11篇 |
1990年 | 13篇 |
1989年 | 12篇 |
1988年 | 6篇 |
1987年 | 3篇 |
1986年 | 6篇 |
1985年 | 6篇 |
1984年 | 10篇 |
1983年 | 4篇 |
1982年 | 6篇 |
1981年 | 4篇 |
1980年 | 8篇 |
1979年 | 2篇 |
1978年 | 3篇 |
1977年 | 4篇 |
1976年 | 6篇 |
1974年 | 6篇 |
1970年 | 2篇 |
排序方式: 共有1446条查询结果,搜索用时 31 毫秒
981.
Takashi Ohtsuki Hiroyuki Kikuchi Takashi Koyano Thaworn Kowithayakorn Toshiyuki Sakai Masami Ishibashi 《Bioorganic & medicinal chemistry》2009,17(18):6748-6754
The TRAIL/death-receptor signaling pathway has been considered a promising target for selective cancer therapy, although some malignant tumors exhibit TRAIL resistance. We previously found that isoflavonoid enhanced TRAIL-induced apoptosis in TRAIL-resistant cells, which is achieved through up-regulation of death receptor 5 (DR5). In our screening program targeting DR5 promoter enhancement activity, activity-guided fractionations of the extract of Catimbium speciosum led to the isolation of six compounds. Of the isolates, cardamomin (6), the most potent compound, enhanced the expressions of DR5 and DR4 and decreased the Bcl-xL level in TRAIL-resistant DLD1 cells. The combination of 6 and TRAIL synergistically enhanced TRAIL-induced apoptosis against TRAIL-resistant cells upon the activation of caspase-8, 9, and 3. In addition, enhancement of apoptosis by 6 was inhibited by human recombinant DR5/Fc and DR4/Fc chimera proteins, TRAIL-neutralizing fusion proteins, indicating that 6 sensitize TRAIL-resistant cells to TRAIL through the induction of DR5 and DR4. Also, up-regulation of DR5 by 6 paralleled that of CCAAT/enhancer-binding protein-homologous protein (CHOP). 相似文献
982.
Nozaki H Matsuzaki M Takahara M Misumi O Kuroiwa H Hasegawa M Shin-i T Kohara Y Ogasawara N Kuroiwa T 《Journal of molecular evolution》2003,56(4):485-497
Abstract
Red algae are one of the main photosynthetic eukaryotic lineages and are characterized by primitive features, such as a lack
of flagella and the presence of phycobiliproteins in the chloroplast. Recent molecular phylogenetic studies using nuclear
gene sequences suggest two conflicting hypotheses (monophyly versus non-monophyly) regarding the relationships between red
algae and green plants. Although kingdom-level phylogenetic analyses using multiple nuclear genes from a wide-range of eukaryotic
lineages were very recently carried out, they used highly divergent gene sequences of the cryptomonad nucleomorph (as the
red algal taxon) or incomplete red algal gene sequences. In addition, previous eukaryotic phylogenies based on nuclear genes
generally included very distant archaebacterial sequences (designated as the outgroup) and/or amitochondrial organisms, which
may carry unusual gene substitutions due to parasitism or the absence of mitochondria. Here, we carried out phylogenetic analyses
of various lineages of mitochondria-containing eukaryotic organisms using nuclear multigene sequences, including the complete
sequences from the primitive red alga Cyanidioschyzon merolae. Amino acid sequence data for two concatenated paralogous genes (α- and β-tubulin) from mitochondria-containing organisms
robustly resolved the basal position of the cellular slime molds, which were designated as the outgroup in our phylogenetic
analyses. Phylogenetic analyses of 53 operational taxonomic units (OTUs) based on a 1525-amino-acid sequence of four concatenated
nuclear genes (actin, elongation factor-1α, α-tubulin, and β-tubulin) reliably resolved the phylogeny only in the maximum
parsimonious (MP) analysis, which indicated the presence of two large robust monophyletic groups (Groups A and B) and the
basal eukaryotic lineages (red algae, true slime molds, and amoebae). Group A corresponded to the Opisthokonta (Metazoa and
Fungi), whereas Group B included various primary and secondary plastid-containing lineages (green plants, glaucophytes, euglenoids,
heterokonts, and apicomplexans), Ciliophora, Kinetoplastida, and Heterolobosea. The red algae represented the sister lineage
to Group B. Using 34 OTUs for which essentially the entire amino acid sequences of the four genes are known, MP, distance,
quartet puzzling, and two types of maximum likelihood (ML) calculations all robustly resolved the monophyly of Group B, as
well as the basal position of red algae within eukaryotic organisms. In addition, phylogenetic analyses of a concatenated
4639-amino-acid sequence for 12 nuclear genes (excluding the EF-2 gene) of 12 mitochondria-containing OTUs (including C. merolae) resolved a robust non-sister relationship between green plants and red algae within a robust monophyletic group composed
of red algae and the eukaryotic organisms belonging to Group B. A new scenario for the origin and evolution of plastids is
suggested, based on the basal phylogenetic position of the red algae within the large clade (Group B plus red algae). The
primary plastid endosymbiosis likely occurred once in the common ancestor of this large clade, and the primary plastids were
subsequently lost in the ancestor(s) of the Discicristata (euglenoids, Kinetoplastida, and Heterolobosea), Heterokontophyta,
and Alveolata (apicomplexans and Ciliophora). In addition, a new concept of “Plantae” is proposed for phototrophic and nonphototrophic
organisms belonging to Group B and red algae, on the basis of the common history of the primary plastid endosymbiosis. The
Plantae include primary plastid-containing phototrophs and nonphototrophic eukaryotes that possibly contain genes of cyanobacterial
origin acquired in the primary endosymbiosis. 相似文献
983.
Muraki T Taki M Hasegawa Y Iwaki H Lau PC 《Applied and environmental microbiology》2003,69(3):1564-1572
The 2-nitrobenzoic acid degradation pathway of Pseudomonas fluorescens strain KU-7 proceeds via a novel 3-hydroxyanthranilate intermediate. In this study, we cloned and sequenced a 19-kb DNA locus of strain KU-7 that encompasses the 3-hydroxyanthranilate meta-cleavage pathway genes. The gene cluster, designated nbaEXHJIGFCDR, is organized tightly and in the same direction. The nbaC and nbaD gene products were found to be novel homologs of the eukaryotic 3-hydroxyanthranilate 3,4-dioxygenase and 2-amino-3-carboxymuconate-6-semialdehyde decarboxylase, respectively. The NbaC enzyme carries out the oxidation of 3-hydroxyanthranilate to 2-amino-3-carboxymuconate-6-semialdehyde, while the NbaD enzyme catalyzes the decarboxylation of the latter compound to 2-aminomuconate-6-semialdehyde. The NbaC and NbaD proteins were overexpressed in Escherichia coli and characterized. The substrate specificity of the 23.8-kDa NbaC protein was found to be restricted to 3-hydroxyanthranilate. In E. coli, this enzyme oxidizes 3-hydroxyanthranilate with a specific activity of 8 U/mg of protein. Site-directed mutagenesis experiments revealed the essential role of two conserved histidine residues (His52 and His96) in the NbaC sequence. The NbaC activity is also dependent on the presence of Fe(2+) but is inhibited by other metal ions, such as Zn(2+), Cu(2+), and Cd(2+). The NbaD protein was overproduced as a 38.7-kDa protein, and its specific activity towards 2-amino-3-carboxymuconate-6-semialdehyde was 195 U/mg of protein. Further processing of 2-aminomuconate-6-semialdehyde to pyruvic acid and acetyl coenzyme A was predicted to proceed via the activities of NbaE, NbaF, NbaG, NbaH, NbaI, and NbaJ. The predicted amino acid sequences of these proteins are highly homologous to those of the corresponding proteins involved in the metabolism of 2-aminophenol (e.g., AmnCDEFGH in Pseudomonas sp. strain AP-3). The NbaR-encoding gene is predicted to have a regulatory function of the LysR family type. The function of the product of the small open reading frame, NbaX, like the homologous sequences in the nitrobenzene or 2-aminophenol metabolic pathway, remains elusive. 相似文献
984.
cGMP-specific, cGMP-binding phosphodiesterase (PDE5) regulates such physiological processes as smooth muscle relaxation and neuronal survival. PDE5 contains two N-terminal domains (GAF A and GAF B), but the functional roles of these domains have not been determined. Here we show that recombinant PDE5 is activated directly upon cGMP binding to the GAF A domain, and this effect does not require PDE5 phosphorylation. PDE5 exhibited time- and concentration-dependent reversible activation in response to cGMP, with the highest activation (9- to 11-fold) observed at low substrate concentrations (0.1 micro M cGMP). A monoclonal antibody directed against GAF A blocked cGMP binding, prevented PDE5 activation and decreased basal activity, revealing that PDE5 in its non-activated state has low intrinsic catalytic activity. Activated PDE5 showed higher sensitivity towards sildenafil than non-activated PDE5. The stimulatory effect of cGMP binding on the catalytic activity of PDE5 suggests that this mechanism of enzyme activation may be common among other GAF domain-containing proteins. The data also suggest that development of agonists and antagonists of PDE5 activity based on binding to this site might be possible. 相似文献
985.
Mutation and expression of the p53 gene during chemical hepatocarcinogenesis in F344 rats 总被引:5,自引:0,他引:5
Fu Y Deng W Kawarada Y Kawagoe M Ma YZ Li X Guo N Kameda T Terada K Sugiyama T 《Biochimica et biophysica acta》2003,1628(1):40-49
Inactivation of the p53 gene is one of the most frequent genetic alterations in carcinogenesis. We studied gene mutations, the mRNA expression of p53, and the accumulation of p53 protein in chemical hepatocarcinogenesis in rats. Samples consisting of 44 precancerous foci and 18 cancerous foci were collected by laser capture microdissection (LCM), and analyzed for mutations in rat p53 gene exons 5-8 by PCR-single-strand conformational polymorphism (PCR-SSCP). We found that 25 PCR-SSCP bands of exons 6/7 and 8 were altered in 22/62 (35.4%) LCM samples. Direct p53 gene sequencing showed that 20/62 (9 precancer, 11 cancer) (32.3%) LCM samples exhibited 34 point mutations. Ten LCM samples exhibited double or triple mutations in exons 6/7 and 8 simultaneously. A quantitative analysis of p53 mRNA showed that p53 mRNA peaked at an early stage (week 6) in the precancerous lesion, 20 times that of adjacent normal tissue, and returned to normal by week 23. Similar to precancer, p53 mRNA in cancer was five times as high as that of adjacent normal tissue at week 12, and was closer to normal at week 23. When p53 mRNA declined from a high to low, positive immunostaining for the p53 protein began to be seen in precancerous and cancerous foci, suggesting that the p53 protein had accumulated in these foci. Results show that p53 gene mutation is present in initial chemical hepatocarcinogenesis and p53 mRNA concentration is clearly elevated before gene mutation. Once the p53 gene has mutated, mRNA concentration progressively declines, suggesting that mutation leads to inactivation of the p53 gene. 相似文献
986.
Kobayashi TK Ueda M Nishino T Muramatsu M Moritani S Seki H Araki H Kaneko C 《Acta cytologica》2003,47(6):1069-1073
BACKGROUND: Pseudosarcomatous fibromyxoid tumor (PFT) of the urinary bladder is an uncommon benign lesion that can involve any site in the bladder. Cellular features of PFT of the bladder are exceedingly rare. We describe the urinary cytology in a PFT patient who displayed numerous papillary fragments that suggested a malignant tumor. CASE: A 52-year-old man was seen at the hospital for evaluation of gross hematuria. At cystoscopy, the urologist observed a 3-cm, smooth, polypoid and ulcerated mass extending from the trigone to the bladder neck. Urinary cytology showed many papillary clusters with irregular nuclear margins in the bloody cell background. No spindle cells were noted. Cytology was interpreted as papillary growth, factor transitional cell carcinoma, grade 2-3. A laparotomy with partial resection of the urinary bladder was carried out, and histologically the tumor was composed of spindle, stellate, fibroblastic cells embedded in myxoid stroma with little collagen. Immunohistochemical and ultrastructural studies revealed the fibroblastic nature of the lesion. The final diagnosis was PFT of the bladder on the basis of histologic examination of the resected material. CONCLUSION: Papillary fragments are a diagnostic pitfall in urinary cytology of PFT lesions. 相似文献
987.
Sumino H Ichikawa S Itoh H Utsugi T Ohyama Y Umeda M Nakamura T Kanda T Mizunuma H Tomono S Murakami M Kurabayashi M 《Hormone research》2003,60(3):134-142
OBJECTS: To investigate the effect of combined estrogen and progesterone therapy on insulin resistance (IR) and carbohydrate and lipid metabolism in postmenopausal women (PMW) with impaired (IGT) and normal glucose tolerance (NGT). METHODS: Sixteen Japanese PMW with IGT and 33 with NGT received daily oral hormone replacement therapy (HRT; 0.625 mg of conjugated equine estrogen plus 2.5 mg of medroxyprogesterone acetate) for 12 months. As controls, 13 Japanese PMW with IGT and 31 with NGT were enrolled and not treated by HRT. Fasting plasma glucose (FPG), fasting immunoreactive insulin (IRI), and IR were measured in each subject at study initiation and 12 months later. We used homeostasis model assessment (HOMA) to determine IR. RESULTS: FPG and HOMA IR were decreased in both HRT groups, and fasting IRI was reduced in the HRT-NGT group. In controls, FPG, fasting IRI, and HOMA IR were unaltered. Total and low-density lipoprotein cholesterol were decreased and high-density lipoprotein cholesterol was increased in both HRT groups, but triglyceride was unchanged. In controls, lipid metabolism was unaltered. CONCLUSION: HRT decreased IR and improved carbohydrate and lipid metabolism in Japanese PMW with IGT and NGT. These beneficial effects argue for the use of HRT in PMW with IGT as well as NGT. 相似文献
988.
Nikaido M Cao Y Harada M Okada N Hasegawa M 《Molecular phylogenetics and evolution》2003,28(2):276-284
We sequenced the complete mitochondrial (mt) genomes of three insectivores: the long-eared hedgehog Hemiechinus auritus, the Japanese mole Mogera wogura, and the greater Japanese shrew-mole Urotrichus talpoides. These mtDNA data together with other previously sequenced mtDNAs were analyzed using a maximum likelihood method to infer their phylogenetic relationships among eutherians. Previous mitochondrial protein analyses used a simple model that did not consider site-heterogeneity, and Erinaceoidea (hedgehogs and moonrats) was placed at the basal eutherian position that is separated from Soricoidea (shrews) and Talpoidea (moles), suggesting the exclusion of the Erinaceoidea-Eulipotyphla tree. By including the new mtDNA sequences and introducing site-heterogeneity into the model, the Erinaceoidea-Eulipotyphla tree emerges as the best tree or as a tree with a log-likelihood score indistinguishable from that of the best tree. However, this conclusion depends on species sampling in Erinaceoidea, demonstrating the importance of both species sampling and use of an appropriate substitution model when inferring phylogenetic relationships. 相似文献
989.
Kakita M Shimizu T Emoto M Nagai M Takeguchi M Hosono Y Kume N Ozawa T Ueda M Bhuiyan MS Matsuo Y 《Genes & genetic systems》2003,78(5):383-389
The repeating units of the histone gene cluster containing the H1, H2A, H2B and H4 genes were amplified by PCR from the Drosophila melanogaster species subgroup, i.e., D. yakuba, D. erecta, D. sechellia, D. mauritiana, D. teissieri and D. orena. The PCR products were cloned and their nucleotide sequences of about 4.6-4.8kbp were determined to elucidate the mechanism of molecular evolution of the histone gene family. The heterogeneity among the histone gene repeating units was 0.6% and 0.7% for D. yakuba and D. sechellia, respectively, indicating the same level of heterogeneity as in the H3 gene region of D. melanogaster. Divergence of the genes among species even in the most closely related ones was much greater than the heterogeneity among family members, indicating a concerted mode of evolution for the histone gene repeating units. Among the species in the D. melanogaster species subgroup, the histone gene regions as well as 3rd codon position of the coding region showed nearly the same GC contents. These results suggested that the previous conclusion on analysis of the H3 gene regions, the gene family evolution in a concerted fashion, holds true for the whole histone gene repeating unit. 相似文献
990.
Motomi?Genkai-KatoEmail author Kentaro?Nozaki Pavel P.?Sherstyankin Natalia P.?Logacheva Nina A.?Bondarenko Shuji?Hino Masami?Nakanishi 《Limnology》2003,4(2):113-117
We examined the photosynthetic activity of the phytoplankton community collected from the surface to a depth of 1000m in the south basin of Lake Baikal. Experiments were conducted in June (mixing period) and August (stratified period). The carbon fixation rate was measured by the use of a 13C tracer after the incubation of samples under light conditions in the upper water column. Photosynthetic fixation of 13C was detected for samples collected from a depth of 500m, indicating the viability of phytoplankton in deep water. The community composition was dominated by Bacillariophyceae in deep water. The finding of lower activity at a depth of 200m than that at a depth of 500m in August suggests that the spring diatom bloom could be a significant source of viable populations at a depth of 500m. Photosynthetic activity was not detected in samples collected at a depth of 1000m. 相似文献