全文获取类型
收费全文 | 1804篇 |
免费 | 76篇 |
出版年
2022年 | 16篇 |
2021年 | 14篇 |
2020年 | 13篇 |
2019年 | 9篇 |
2018年 | 11篇 |
2017年 | 15篇 |
2016年 | 25篇 |
2015年 | 31篇 |
2014年 | 42篇 |
2013年 | 152篇 |
2012年 | 74篇 |
2011年 | 88篇 |
2010年 | 61篇 |
2009年 | 69篇 |
2008年 | 89篇 |
2007年 | 97篇 |
2006年 | 123篇 |
2005年 | 99篇 |
2004年 | 89篇 |
2003年 | 92篇 |
2002年 | 120篇 |
2001年 | 39篇 |
2000年 | 31篇 |
1999年 | 35篇 |
1998年 | 26篇 |
1997年 | 24篇 |
1996年 | 21篇 |
1995年 | 20篇 |
1994年 | 19篇 |
1993年 | 17篇 |
1992年 | 36篇 |
1991年 | 25篇 |
1990年 | 27篇 |
1989年 | 21篇 |
1988年 | 23篇 |
1987年 | 19篇 |
1986年 | 17篇 |
1985年 | 21篇 |
1984年 | 16篇 |
1983年 | 8篇 |
1982年 | 11篇 |
1981年 | 12篇 |
1980年 | 6篇 |
1979年 | 4篇 |
1978年 | 8篇 |
1977年 | 12篇 |
1976年 | 12篇 |
1975年 | 12篇 |
1974年 | 11篇 |
1973年 | 7篇 |
排序方式: 共有1880条查询结果,搜索用时 31 毫秒
81.
Taeko Kimura Koji Tsutsumi Masato Taoka Taro Saito Masami Masuda-Suzukake Koichi Ishiguro Florian Plattner Takafumi Uchida Toshiaki Isobe Masato Hasegawa Shin-ichi Hisanaga 《The Journal of biological chemistry》2013,288(11):7968-7977
Neurodegenerative diseases associated with the pathological aggregation of microtubule-associated protein Tau are classified as tauopathies. Alzheimer disease, the most common tauopathy, is characterized by neurofibrillary tangles that are mainly composed of abnormally phosphorylated Tau. Similar hyperphosphorylated Tau lesions are found in patients with frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) that is induced by mutations within the tau gene. To further understand the etiology of tauopathies, it will be important to elucidate the mechanism underlying Tau hyperphosphorylation. Tau phosphorylation occurs mainly at proline-directed Ser/Thr sites, which are targeted by protein kinases such as GSK3β and Cdk5. We reported previously that dephosphorylation of Tau at Cdk5-mediated sites was enhanced by Pin1, a peptidyl-prolyl isomerase that stimulates dephosphorylation at proline-directed sites by protein phosphatase 2A. Pin1 deficiency is suggested to cause Tau hyperphosphorylation in Alzheimer disease. Up to the present, Pin1 binding was only shown for two Tau phosphorylation sites (Thr-212 and Thr-231) despite the presence of many more hyperphosphorylated sites. Here, we analyzed the interaction of Pin1 with Tau phosphorylated by Cdk5-p25 using a GST pulldown assay and Biacore approach. We found that Pin1 binds and stimulates dephosphorylation of Tau at all Cdk5-mediated sites (Ser-202, Thr-205, Ser-235, and Ser-404). Furthermore, FTDP-17 mutant Tau (P301L or R406W) showed slightly weaker Pin1 binding than non-mutated Tau, suggesting that FTDP-17 mutations induce hyperphosphorylation by reducing the interaction between Pin1 and Tau. Together, these results indicate that Pin1 is generally involved in the regulation of Tau hyperphosphorylation and hence the etiology of tauopathies. 相似文献
82.
Shin-ichi Ikeda Yoshifumi Tamura Saori Kakehi Kageumi Takeno Minako Kawaguchi Takahiro Watanabe Fumihiko Sato Takeshi Ogihara Akio Kanazawa Yoshio Fujitani Ryuzo Kawamori Hirotaka Watada 《Biochemical and biophysical research communications》2013
Exercise enhances insulin sensitivity in skeletal muscle, but the underlying mechanism remains obscure. Recent data suggest that alternatively activated M2 macrophages enhance insulin sensitivity in insulin target organs such as adipose tissue and liver. Therefore, the aim of this study was to determine the role of anti-inflammatory M2 macrophages in exercise-induced enhancement of insulin sensitivity in skeletal muscle. C57BL6J mice underwent a single bout of treadmill running (20 m/min, 90 min). Twenty-four hours later, ex vivo insulin-stimulated 2-deoxy glucose uptake was found to be increased in plantaris muscle. This change was associated with increased number of CD163-expressing macrophages (i.e. M2-polarized macrophages) in skeletal muscle. Systemic depletion of macrophages by pretreatment of mice with clodronate-containing liposome abrogated both CD163-positive macrophage accumulation in skeletal muscle as well as the enhancement of insulin sensitivity after exercise, without affecting insulin-induced phosphorylation of Akt and AS160 or exercise-induced GLUT4 expression. These results suggest that accumulation of M2-polarized macrophages is involved in exercise-induced enhancement of insulin sensitivity in mouse skeletal muscle, independently of the phosphorylation of Akt and AS160 and expression of GLUT4. 相似文献
83.
Zhe Nie Victoria Feher Srinivasa Natala Christopher McBride Andre Kiryanov Benjamin Jones Betty Lam Yan Liu Stephen Kaldor Jeffrey Stafford Kouki Hikami Noriko Uchiyama Tomohiro Kawamoto Yuichi Hikichi Shin-ichi Matsumoto Nobuyuki Amano Lilly Zhang David Hosfield Takashi Ichikawa 《Bioorganic & medicinal chemistry letters》2013,23(12):3662-3666
Using structure-based drug design, we identified and optimized a novel series of pyrimidodiazepinone PLK1 inhibitors resulting in the selection of the development candidate TAK-960. TAK-960 is currently undergoing Phase I evaluation in adult patients with advanced solid malignancies. 相似文献
84.
Takenori Tomohiro Hirotsugu Inoguchi Souta Masuda Yasumaru Hatanaka 《Bioorganic & medicinal chemistry letters》2013,23(20):5605-5608
A specific illumination approach has been developed for identification of adenosine triphosphate (ATP)-binding proteins. This strategy utilizes a tandem photoactivatable unit that consists of a diazirine group as a carbene precursor and an o-hydroxycinnamate moiety as a coumarin precursor. The photolysis of diazirine induces a specific cross-link on target proteins and is followed by photoactivation of coumarin generation with a concomitant release of the pre-installed affinity ligand. The ATP, installed with this cross-linker at the γ-position, successfully transferred a coumarin onto ATP-binding proteins using only UV-irradiation. 相似文献
85.
Yuji Nakamura Teppei Fujimoto Yasuyuki Ogawa Hidenori Namiki Sayaka Suzuki Masayoshi Asano Chie Sugita Akiyoshi Mochizuki Shojiro Miyazaki Kazuhiko Tamaki Yoko Nagai Shin-ichi Inoue Takahiro Nagayama Mikio Kato Katsuyoshi Chiba Kiyoshi Takasuna Takahide Nishi 《Bioorganic & medicinal chemistry》2013,21(11):3175-3196
With the aim to address an undesired cardiac issue observed with our related compound in the recently disclosed novel series of renin inhibitors, further chemical modifications of this series were performed. Extensive structure–activity relationships studies as well as in vivo cardiac studies using the electrophysiology rat model led to the discovery of clinical candidate trans-adamantan-1-ol analogue 56 (DS-8108b) as a potent renin inhibitor with reduced potential cardiac risk. Oral administration of single doses of 3 and 10 mg/kg of 56 in cynomolgus monkeys pre-treated with furosemide led to significant reduction of mean arterial blood pressure for more than 12 h. 相似文献
86.
Toshihiro Miyazaki Masako Mori Carolina A. Yoshida Chizuru Ito Kenji Yamatoya Takeshi Moriishi Yosuke Kawai Hisato Komori Tetsuya Kawane Shin-ichi Izumi Kiyotaka Toshimori Toshihisa Komori 《Histochemistry and cell biology》2013,139(2):339-354
Galnt3 belongs to the GalNAc transferase gene family involved in the initiation of mucin-type O-glycosylation. Male Galnt3-deficient (Galnt3 ?/?) mice were infertile, as previously reported by Ichikawa et al. (2009). To investigate the involvement of Galnt3 in spermatogenesis, we examined the differentiation of germ cells in Galnt3 ?/? mice. Galnt3 mRNA was most highly expressed in testis, and Galnt3 protein was localized in the cis-medial parts of the Golgi stacks of spermatocytes and spermatids in the seminiferous tubules. Spermatozoa in Galnt3 ?/? mice were rare and immotile, and most of them had deformed round heads. They exhibited abnormal acrosome and disturbed mitochondria arrangement in the flagella. At the cap phase, proacrosomal vesicles of various sizes, which had not coalesced to form a single acrosomal vesicle, were attached to the nucleus in Galnt3 ?/? mice. TUNEL-positive cells were increased in the seminiferous tubules. The binding of VVA lectin, which recognizes the Tn antigen (GalNAc-O-Ser/Thr), in the acrosomal regions of spermatids and spermatozoa in Galnt3 ?/? mice was drastically reduced. Equatorin is a N, O-sialoglycoprotein localized in the acrosomal membrane and is suggested to be involved in sperm–egg interaction. Immunohistochemical and Western blot analyses showed a drastic reduction in the reactivity with MN9 antibody, which recognizes the O-glycosylated moiety of equatorin and inhibits sperm–egg interaction. These findings indicate that deficiency of Galnt3 results in a severe reduction of mucin-type O-glycans in spermatids and causes impaired acrosome formation, leading to oligoasthenoteratozoospermia, and suggest that Galnt3 may also be involved in the process of fertilization through the O-glycosylation of equatorin. 相似文献
87.
Jiro Arima Yoshitaka Isoda Tadashi Hatanaka Nobuhiro Mori 《World journal of microbiology & biotechnology》2013,29(5):899-906
N-Acyl-d-amino acid amidohydrolases (d-aminoacylases) are often used as tools for the optical resolution of d-amino acids, which are important products with applications in industries related to medicine and cosmetics. For this study, genes encoding d-aminoacylase were cloned from the genomes of Streptomyces spp. using sequence-based screening. They were expressed by Escherichia coli and Streptomyces lividans. Almost all of the cell-free extracts exhibit hydrolytic activity toward N-acetyl-(Ac-)d-Phe (0.05–6.32 μmol min?1 mg?1) under conditions without CoCl2. Addition of 1 mM CoCl2 enhanced their activity. Among them, the highest activity was observed from cell-free extracts prepared from S. lividans that possess the d-aminoacylase gene of Streptomyces sp. 64E6 (specific activities were, respectively, 7.34 and 9.31 μmol min?1 mg?1 for N-Ac-d-Phe and N-Ac-d-Met hydrolysis). Furthermore, when using glycerol as a carbon source for cultivation, the recombinant enzyme from Streptomyces sp. 64E6 was produced in 4.2-fold greater quantities by S. lividans than when using glucose. d-Aminoacylase from Streptomyces sp. 64E6 showed optimum at pH 8.0–9.0. It was stable at pH 5.5–9.0 up to 30 °C. The enzyme hydrolyzed various N-acetyl-d-amino acids that have hydrophobic side chains. In addition, the activity toward N-chloroacetyl-d-Phe was 2.1-fold higher than that toward N-Ac-d-Phe, indicating that the structure of N-acylated portion of substrate altered the activity. 相似文献
88.
Isamu Shiio Shin-ichi Sugimoto Kazue Kawamura 《Bioscience, biotechnology, and biochemistry》2013,77(7):1849-1854
Azaserine-resistant mutants derived from a 5-fluorotryptophan-resistant, l-tryptophan-producing mutant of Brevibacterium flavum, accumulated 10.3 g/liter of l-tryptophan at maximum. The production increased to 11.4 g/liter when l-serine was added. In the mutant, only anthranilate synthase among enzymes of the tryptophan-specific bio synthetic pathway increased in activity to a 2-fold higher level than that in the parent strain, No. 187. Sensitivity of anthranilate synthase to the feedback inhibition was not altered by the mutation. Activity of 3-deoxy-d-arabino-heptulosonate 7-phosphate synthase, the first common enzyme for aromatic amino acid biosynthesis, also increased 2.7-fold and was less sensitive to the feedback inhibition by phenylalanine and tyrosine. Tryptophan transport activity in strain A-100 was similar as that in the parent. Azaserine inhibited anthranilate synthase activity by 50% at 0.075 mm. The inhibition was of a mixed type with respect to both the two substrates. Anthranilate synthase of strain A-100 was inhibited in a similar manner to that of the parent. 相似文献
89.
Akikazu Hatanaka Tadahiko Kajiwara Takatoshi Koda 《Bioscience, biotechnology, and biochemistry》2013,77(10):2115-2117
The substrate specificity of enzyme system producing C6-aldehyde in Thea chloroplasts was clarified with an entire series of synthesized positional isomers, in which the position of cis-1, cis-4-pentadiene system varies from C-3 to C-13 in C18 fatty acid and geometrical isomers of linoleic acid. The structural requirement for the substrate of enzyme system producing C6-aldehyde is the presence of cis-1, cis-4-pentadiene system between ω-6 and ω-10. 相似文献
90.
Jiro Sekiya Tadahiko Kajiwara Akikazu Hatanaka 《Bioscience, biotechnology, and biochemistry》2013,77(3):677-678
A simple electronic device was constructed which, in combination with a conventional titrator, records close approximation of the buffer capacity curve (β-pH curve) for the solution of unknown composition. Since the recorded curves provide the overall picture of the distribution of weak Brönsted acids in the solution on the pKa axis, this apparatus may be useful in various fields such as chemistry of food and agricultural products and clinical medicine, where the characterization of the complex mixtures of weak electrolytes — carboxylic acids, amono acids, proteins, amines, phenols and etc. — are important. 相似文献