全文获取类型
收费全文 | 2861篇 |
免费 | 139篇 |
出版年
2023年 | 6篇 |
2022年 | 16篇 |
2021年 | 48篇 |
2020年 | 16篇 |
2019年 | 35篇 |
2018年 | 41篇 |
2017年 | 32篇 |
2016年 | 48篇 |
2015年 | 82篇 |
2014年 | 81篇 |
2013年 | 185篇 |
2012年 | 188篇 |
2011年 | 177篇 |
2010年 | 117篇 |
2009年 | 120篇 |
2008年 | 204篇 |
2007年 | 217篇 |
2006年 | 181篇 |
2005年 | 165篇 |
2004年 | 205篇 |
2003年 | 162篇 |
2002年 | 154篇 |
2001年 | 69篇 |
2000年 | 48篇 |
1999年 | 40篇 |
1998年 | 33篇 |
1997年 | 30篇 |
1996年 | 19篇 |
1995年 | 21篇 |
1994年 | 12篇 |
1993年 | 16篇 |
1992年 | 29篇 |
1991年 | 32篇 |
1990年 | 17篇 |
1989年 | 23篇 |
1988年 | 17篇 |
1987年 | 7篇 |
1986年 | 11篇 |
1985年 | 9篇 |
1984年 | 10篇 |
1983年 | 10篇 |
1982年 | 9篇 |
1981年 | 5篇 |
1979年 | 8篇 |
1978年 | 5篇 |
1977年 | 5篇 |
1976年 | 6篇 |
1975年 | 6篇 |
1973年 | 6篇 |
1967年 | 4篇 |
排序方式: 共有3000条查询结果,搜索用时 15 毫秒
61.
62.
Katsunori Yanagawa Michinari Sunamura Mark Alexander Lever Yuki Morono Akihiro Hiruta Osamu Ishizaki 《Geomicrobiology journal》2013,30(2):118-129
In this study, we investigated the diversity and spatial distribution of anaerobic methanotrophic archaea (ANMEs) in sediments of a gas hydrate field off Joetsu in the Japan Sea. Distribution of ANMEs in sediments was identified by targeting the gene for methyl coenzyme M reductase alpha subunit (mcrA), a phylogenetically conserved gene that occurs uniquely in methanotrophic and methanogenic archaea, in addition to 16S rRNA genes. Quantitative PCR analyses of mcrA genes in 14 piston core samples suggested that members of ANME-1 group would dominate AOM communities in sulfate-depleted sediments, even below the sulfate-methane interface, while ANME-2 archaea would prefer to populate in shallower sediments containing comparatively higher sulfate concentrations. These results suggest that, although the potential electron acceptors in sulfate-depleted habitats remain elusive, the niche separation of ANME-1 and -2 may be controlled by in situ concentration of sulfate and the availability in sediments. 相似文献
63.
Akihiro Matsuda Kohjiro Nagao Michinori Matsuo Noriyuki Kioka Kazumitsu Ueda 《Journal of neurochemistry》2013,126(1):93-101
High cholesterol turnover catalyzed by cholesterol 24‐hydroxylase is essential for neural functions, especially learning. Because 24(S)‐hydroxycholesterol (24‐OHC), produced by 24‐hydroxylase, induces apoptosis of neuronal cells, it is vital to eliminate it rapidly from cells. Here, using differentiated SH‐SY5Y neuron‐like cells as a model, we examined whether 24‐OHC is actively eliminated via transporters induced by its accumulation. The expression of ABCA1 and ABCG1 was induced by 24‐OHC, as well as TO901317 and retinoic acid, which are ligands of the nuclear receptors liver X receptor/retinoid X receptor (LXR/RXR). When the expression of ABCA1 and ABCG1 was induced, 24‐OHC efflux was stimulated in the presence of high‐density lipoprotein (HDL), whereas apolipoprotein A‐I was not an efficient acceptor. The efflux was suppressed by the addition of siRNA against ABCA1, but not by ABCG1 siRNA. To confirm the role of each transporter, we analyzed human embryonic kidney 293 cells stably expressing human ABCA1 or ABCG1; we clearly observed 24‐OHC efflux in the presence of HDL, whereas efflux in the presence of apolipoprotein A‐I was marginal. Furthermore, the treatment of primary cerebral neurons with LXR/RXR ligands suppressed the toxicity of 24‐OHC. These results suggest that ABCA1 actively eliminates 24‐OHC in the presence of HDL as a lipid acceptor and protects neuronal cells. 相似文献
64.
Masanori Terai Naotaka Izumiyama-Shimomura Junko Aida Naoshi Ishikawa Mie Kuroiwa Steven S.S. Poon Tomio Arai Masashi Toyoda Hidenori Akutsu Akihiro Umezawa Ken-ichi Nakamura Kaiyo Takubo 《Tissue & cell》2013,45(6):407-413
Here we attempted to clarify telomere metabolism in parental cells and their derived clonal human induced pluripotent stem cells (iPSCs) at different passages using quantitative fluorescence in situ hybridization (Q-FISH). Our methodology involved estimation of the individual telomere lengths of chromosomal arms in individual cells within each clone in relation to telomere fluorescence units (TFUs) determined by Q-FISH. TFUs were very variable within the same metaphase spread and within the same cell. TFUs of the established iPSCs derived from human amnion (hAM933 iPSCs), expressed as mean values of the median TFUs of 20 karyotypes, were significantly longer than those of the parental cells, although the telomere extension rates varied quite significantly among the clones. Twenty metaphase spreads from hAM933 iPSCs demonstrated no chromosomal instability. The iPSCs established from fetal lung fibroblasts (MRC-5) did not exhibit telomere shortening and chromosomal instability as the number of passages increased. However, the telomeres of other iPSCs derived from MRC-5 became shorter as the number of passages increased, and one (5%) of 20 metaphase spreads showed chromosomal abnormalities including X trisomy at an early stage and all 20 showed abnormalities including X and 12 trisomies at the late stage. 相似文献
65.
Akiharu Kubo Aiko Shiohama Takashi Sasaki Kazuhiko Nakabayashi Hiroshi Kawasaki Toru Atsugi Showbu Sato Atsushi Shimizu Shuji Mikami Hideaki Tanizaki Masaki Uchiyama Tatsuo Maeda Taisuke Ito Jun-ichi Sakabe Toshio Heike Torayuki Okuyama Rika Kosaki Kenjiro Kosaki Jun Kudoh Kenichiro Hata Akihiro Umezawa Yoshiki Tokura Akira Ishiko Hironori Niizeki Kenji Kabashima Yoshihiko Mitsuhashi Masayuki Amagai 《American journal of human genetics》2013,93(5):945-956
“Nagashima-type” palmoplantar keratosis (NPPK) is an autosomal recessive nonsyndromic diffuse palmoplantar keratosis characterized by well-demarcated diffuse hyperkeratosis with redness, expanding on to the dorsal surfaces of the palms and feet and the Achilles tendon area. Hyperkeratosis in NPPK is mild and nonprogressive, differentiating NPPK clinically from Mal de Meleda. We performed whole-exome and/or Sanger sequencing analyses of 13 unrelated NPPK individuals and identified biallelic putative loss-of-function mutations in SERPINB7, which encodes a cytoplasmic member of the serine protease inhibitor superfamily. We identified a major causative mutation of c.796C>T (p.Arg266∗) as a founder mutation in Japanese and Chinese populations. SERPINB7 was specifically present in the cytoplasm of the stratum granulosum and the stratum corneum (SC) of the epidermis. All of the identified mutants are predicted to cause premature termination upstream of the reactive site, which inhibits the proteases, suggesting a complete loss of the protease inhibitory activity of SERPINB7 in NPPK skin. On exposure of NPPK lesional skin to water, we observed a whitish spongy change in the SC, suggesting enhanced water permeation into the SC due to overactivation of proteases and a resultant loss of integrity of the SC structure. These findings provide an important framework for developing pathogenesis-based therapies for NPPK. 相似文献
66.
Takao Morita Akihiro NezuYosuke Tojyo Akihiko Tanimura 《Biochemical and biophysical research communications》2013
Adenoviruses have been used for gene transfer to salivary gland cells in vivo. Their use to study the function of salivary acinar cells was limited by a severe inflammatory response and by the destruction of fluid-secreting acinar cells. In the present study, low doses of adenovirus were administered to express Stim1-mKO1 by retrograde ductal injection to submandibular glands. The approach succeeded in increasing muscarinic stimulation-induced Ca2+ responses in acinar cells without inflammation or decreased salivary secretions. This increased Ca2+ response was notable upon weak muscarinic stimulation and was attributed to increased Ca2+ release from internal stores and increased Ca2+ entry. The basal Ca2+ level was higher in Stim1-mKO1-expressing cells than in mKO1-expressing and non-expressing cells. Exposure of permeabilized submandibular acinar cells, where Ca2+ concentration was fixed at 50 nM, to inositol 1,4,5-trisphosphate (IP3) produced similar effects on the release of Ca2+ from stores in Stim1-mKO1-expressing and non-expressing cells. The low toxicity and relative specificity to acinar cells of the mild gene transfer method described herein are particularly useful for studying the molecular functions of salivary acinar cells in vivo, and may be applied to increase salivary secretions in experimental animals and human in future. 相似文献
67.
Ryuji Asano Amon Nagami Yuki Fukumoto Futoshi Yazama Hideyuki Ito Isao Sakata Akihiro Tai 《Bioorganic & medicinal chemistry》2013,21(8):2298-2304
Three new water-soluble chlorin derivatives 3, 5 and 8 for potential use as photosensitizers in photodynamic therapy (PDT) for cancer were synthesized from photoprotoporphyrin IX dimethyl ester (1). The in vivo biodistribution and clearance of chlorin derivatives 3, 5 and 8 were investigated in tumor-bearing mice. Iminodiacetic acid derivative 8 showed the greatest tumor-selective accumulation among the new chlorin derivatives with maximum accumulation in tumor tissue at 3 h after intravenous injection and rapid clearance from normal tissues within 24 h after injection. The in vivo therapeutic efficacy of PDT using 8 was evaluated by measuring tumor growth rates in tumor-bearing mice with 660 nm light-emitting diode irradiation at 3 h after injection of 8. Tumor growth was significantly inhibited by PDT using 8. These results indicate that iminodiacetic acid derivative 8 is useful as a new photosensitizer to overcome the disadvantages of photosensitizers that are currently in clinical use. 相似文献
68.
Masaki Wakasugi Hiroaki Gouda Tomoyasu Hirose Akihiro Sugawara Tsuyoshi Yamamoto Kazuro Shiomi Toshiaki Sunazuka Satoshi Ōmura Shuichi Hirono 《Bioorganic & medicinal chemistry》2013,21(11):3214-3220
Human acidic mammalian chitinase (hAMCase) was recently shown to be involved in the development of asthma, suggesting a possible application for hAMCase inhibitors as novel therapeutic agents for asthma. We therefore initiated drug discovery research into hAMCase using a combination of in silico methodologies and a hAMCase assay system. We first selected 23 candidate hAMCase inhibitors from a database of four million compounds using a multistep screening system combining Tripos Topomer Search technology, a docking calculation and two-dimensional molecular similarity analysis. We then measured hAMCase inhibitory activity of the selected compounds and identified seven compounds with IC50 values ?100 μM. A model describing the binding modes of these hit compounds to hAMCase was constructed, and we discuss the structure–activity relationships of the compounds we identified, suggested by the model and the actual inhibitory activities of the compounds. 相似文献
69.
70.
Keisuke Yoshikawa Yoshihiro Kita Ayako Furukawa Noriko Kawamura Sanae Hasegawa-Ishii Yoichi Chiba Shiro Takei Kei Maruyama Takao Shimizu Atsuyoshi Shimada 《Prostaglandins, leukotrienes, and essential fatty acids》2013,88(5):373-381
Excitotoxicity is involved in neurodegenerative conditions. We investigated the pathological significance of a surge in prostaglandin production immediately after kainic acid (KA) administration [initial phase], followed by a sustained moderate elevation in prostaglandin level [late phase] in the hippocampus of juvenile rats. Numerous pyknotic hippocampal neurons were observed 72 h after KA treatment; this number remained elevated on days 10 and 30. Gross hippocampal atrophy was observed on days 10 and 30. Pre-treatment with indomethacin ameliorated neuronal death on days 10 and 30, and prevented hippocampal atrophy on day 30. Microglial response was moderated by the indomethacin pre-treatment. Blockade of only late-phase prostaglandin production by post-treatment with indomethacin ameliorated neuronal death on day 30. These findings suggest a role for initial-phase prostaglandin production in chronic progressive neuronal death, which is exacerbated by late-phase prostaglandin production. Blockade of prostaglandin production has therapeutic implications in preventing long-term neurological sequelae following excitotoxic brain damage. 相似文献