全文获取类型
收费全文 | 1134篇 |
免费 | 84篇 |
出版年
2022年 | 4篇 |
2019年 | 8篇 |
2018年 | 9篇 |
2016年 | 7篇 |
2015年 | 26篇 |
2014年 | 40篇 |
2013年 | 70篇 |
2012年 | 82篇 |
2011年 | 72篇 |
2010年 | 39篇 |
2009年 | 34篇 |
2008年 | 51篇 |
2007年 | 62篇 |
2006年 | 64篇 |
2005年 | 89篇 |
2004年 | 68篇 |
2003年 | 61篇 |
2002年 | 68篇 |
2001年 | 36篇 |
2000年 | 25篇 |
1999年 | 25篇 |
1998年 | 14篇 |
1997年 | 12篇 |
1996年 | 5篇 |
1995年 | 10篇 |
1994年 | 10篇 |
1993年 | 7篇 |
1992年 | 18篇 |
1991年 | 21篇 |
1990年 | 11篇 |
1989年 | 16篇 |
1988年 | 19篇 |
1987年 | 14篇 |
1986年 | 12篇 |
1985年 | 8篇 |
1984年 | 8篇 |
1983年 | 12篇 |
1982年 | 6篇 |
1981年 | 6篇 |
1980年 | 4篇 |
1979年 | 12篇 |
1978年 | 5篇 |
1976年 | 5篇 |
1975年 | 7篇 |
1973年 | 4篇 |
1971年 | 3篇 |
1970年 | 3篇 |
1968年 | 4篇 |
1966年 | 3篇 |
1965年 | 4篇 |
排序方式: 共有1218条查询结果,搜索用时 15 毫秒
21.
Yuusuke Tamura Kyouhei Hayashi Naoki Omori Yuji Nishiura Kana Watanabe Nobuyuki Tanaka Masahiko Fujioka Naoki Kouyama Akira Yukimasa Yukari Tanaka Takeshi Chiba Hideki Tanioka Hirohide Nambu Hideo Yukioka Hiroki Sato Takayuki Okuno 《Bioorganic & medicinal chemistry letters》2013,23(1):90-95
Optimization of HTS hit 1 for NPY Y5 receptor binding affinity, CYP450 inhibition, solubility and metabolic stability led to the identification of some orally available oxygen-linker derivatives for in vivo study. Among them, derivative 4i inhibited food intake induced by the NPY Y5 selective agonist, and chronic oral administration of 4i in DIO mice caused a dose-dependent reduction of body weight gain. 相似文献
22.
Keisuke Kirita Genichiro Ishii Rie Matsuwaki Yuki Matsumura Shigeki Umemura Shingo Matsumoto Kiyotaka Yoh Seiji Niho Koichi Goto Hironobu Ohmatsu Yuichiro Ohe Kanji Nagai Atsushi Ochiai 《PloS one》2013,8(12)
Background
Intralymphatic tumors in the extratumoral area are considered to represent the preceding phase of lymph node metastasis. The aim of this study was to clarify the biological properties of intralymphatic tumors susceptible to the development of lymph node metastasis, with special reference to the expression of cancer initiating/stem cell (CIC/CSC) related markers in cancer cells and the number of infiltrating stromal cells.Material and Methods
Primary lung adenocarcinomas with lymphatic permeation in the extratumoral area were retrospectively examined (n = 107). We examined the expression levels of CIC/CSC related markers including ALDH1, OCT4, NANOG, SOX2 and Caveolin-1 in the intralymphatic cancer cells to evaluate their relationship to lymph node metastasis. Moreover, the number of infiltrating stromal cells expressing CD34, α-smooth muscle actin, and CD204 were also evaluated.Results
Among the intralymphatic tissues, low ALDH1 expression in cancer cells, high SOX2 expression in cancer cells, and a high number of CD204(+) macrophages were independent predictive factors for lymph node metastasis (P = 0.004, P = 0.008, and P = 0.028, respectively). Among these factors, only low ALDH1 expression in cancer cells was significantly correlated with the farther spreading of lymph node metastasis (mediastinal lymph node, pathological N2) (P = 0.046) and the metastatic lymph node ratio (metastatic/resected) (P = 0.028). On the other hand, in the primary tumors, ALDH1 expression in the cancer cells was not associated with lymph node metastasis. Intralymphatic cancer cells expressing low ALDH1 levels exhibited lower E-cadherin expression levels than cancer cells with high levels of ALDH1 expression (P = 0.015).Conclusions
Intralymphatic cancer cells expressing low levels of ALDH1 and infiltrating macrophages expressing CD204 have a critical impact on lymph node metastasis. Our study also highlighted the significance of evaluating the biological properties of intralymphatic tumors for tumor metastasis. 相似文献23.
24.
Hitoshi Matsuki Hiroko Okuno Fumihiko Sakano Masataka Kusube Shoji Kaneshina 《生物化学与生物物理学报:生物膜》2005,1712(1):92-100
The bilayer phase transitions of three kinds of phospholipids, dipalmitoylphosphatidylcholine (DPPC), distearoylphosphatidylcholine (DSPC) and dihexadecylphosphatidylcholine (DHPC), in deuterium oxide (D2O) and hydrogen oxide (H2O) were observed by differential scanning calorimetry (DSC) under ambient pressure and light-transmittance measurements under high pressure. The DSC measurements showed that the substitution of H2O by D2O affected the pretransition temperatures and the main-transition enthalpies of all PC bilayers. The temperature-pressure phase diagrams for these PC bilayer membranes in both solvents were constructed by use of the data of light-transmittance measurements. Regarding the main transition of all PC bilayer membranes, there was no appreciable difference between the transition temperatures in D2O and H2O under high pressure. On the other hand, the phase transitions among the gel phases including the pretransition were significantly affected by the solvent substitution. The thermodynamic quantities of phase transitions for the PC bilayer membranes were evaluated and the differences in thermodynamic properties by the water substitution were considered from the difference of interfacial-free energy per molecule in the bilayer in both solvents. It was proved that the substitution of H2O by D2O causes shrinkage of the molecular area of phospholipid at bilayer interface due to the difference in bond strength between deuterium and hydrogen bonds and produces the great influence on the bilayer phase with the smaller area. Further, the induction of bilayer interdigitation in D2O turned out to need higher pressures than in H2O. 相似文献
25.
F1-ATPase is the water-soluble part of ATP synthase and is an ATP-driven rotary molecular motor that rotates the rotary shaft against the surrounding stator ring, hydrolyzing ATP. Although the mechanochemical coupling mechanism of F1-ATPase has been well studied, the molecular details of individual reaction steps remain unclear. In this study, we conducted a single-molecule rotation assay of F1 from thermophilic bacteria under various pressures from 0.1 to 140 MPa. Even at 140 MPa, F1 actively rotated with regular 120° steps in a counterclockwise direction, showing high conformational stability and retention of native properties. Rotational torque was also not affected. However, high hydrostatic pressure induced a distinct intervening pause at the ATP-binding angles during continuous rotation. The pause was observed under both ATP-limiting and ATP-saturating conditions, suggesting that F1 has two pressure-sensitive reactions, one of which is evidently ATP binding. The rotation assay using a mutant F1(βE190D) suggested that the other pressure-sensitive reaction occurs at the same angle at which ATP binding occurs. The activation volumes were determined from the pressure dependence of the rate constants to be +100 Å3 and +88 Å3 for ATP binding and the other pressure-sensitive reaction, respectively. These results are discussed in relation to recent single-molecule studies of F1 and pressure-induced protein unfolding. 相似文献
26.
Yuji Inoue Ritsuko Kubota-Koketsu Akifumi Yamashita Mitsuhiro Nishimura Shoji Ideno Ken-ichiro Ono Yoshinobu Okuno Kazuyoshi Ikuta 《The Journal of biological chemistry》2013,288(7):4981-4990
The development of vaccination methods that can overcome the emergence of new types of influenza strains caused by escape mutations is desirable to avoid future pandemics. Here, a novel type of immunogen was designed that targeted the conformation of a highly conserved region of influenza A virus hemagglutinin (HA) composed of two separate sequences that associate to form an anti-parallel β-sheet structure. Our previous study identified this β-sheet region as the structural core in the epitope of a characteristic antibody (B-1) that strongly neutralizes a wide variety of strains within the H3N2 serotype, and therefore this β-sheet region was considered a good target to induce broadly reactive immunity against the influenza A virus. To design the immunogen, residues derived from the B-1 epitope were introduced directly onto a part of enhanced green fluorescent protein (EGFP), whose surface is mostly composed of β-sheets. Through site-directed mutagenesis, several modified EGFPs with an epitope-mimicking structure embedded in their surface were prepared. Two EGFP variants, differing from wild-type (parental) EGFP by only five and nine residues, induced mice to produce antibodies that specifically bind to H3-type HA and neutralize H3N2 virus. Moreover, three of five mice immunized with each of these EGFP variants followed by a booster with equivalent mCherry variants acquired anti-viral immunity against challenge with H3N2 virus at a lethal dosage. In contrast to conventional methods, such as split HA vaccine, preparation of this type of immunogen requires less time and is therefore expected to be quickly responsive to newly emerged influenza viral strains. 相似文献
27.
Kei Arima Hisayoshi Okazaki Hiroko Ono Kiyotaka Yamada Teruhiko Beppu 《Bioscience, biotechnology, and biochemistry》2013,77(10):2313-2317
A mutant of Streptomyces fradiae which requires oleic acid for neomycin formation was isolated and the effects of exogenous fatty acids and other additives on the formation of neomycin were studied. Palmitic acid and high concentration of sodium ions could replace oleic acid in neomycin formation. The fatty acid spectrum of the mutant strain ST–5B was quite different from that of the parent strain 3123. The major fatty acid components of the mutant and the parent were anteiso 15:0 and iso 16: 0, respectively. However the fatty acid composition of the mutant was changed from the anteiso 15: 0-type to the parental iso 16: 0-type by the supplement of oleic acid or high concentration of sodium ions in the medium. In the case of palmitic acid, the major fatty acid component of the mutant cells was changed from anteriso 15: 0 to normal 16:0. The role of these additives in neomycin formation by the mutant is discussed. 相似文献
28.
Fumiya Noguchi Masaru Kawato Takao Yoshida Yoshihiro Fujiwara Katsunori Fujikura Kiyotaka Takishita 《The Journal of eukaryotic microbiology》2013,60(2):158-165
It has recently been unveiled that a wide variety of microbial eukaryotes (protists) occur in chemosynthetic ecosystems, such as hydrothermal vents and methane seeps. However, there is little knowledge regarding protists associated with endemic animals inhabiting these environments. In the present study, utilizing PCR techniques, we detected fragments of the small subunit ribosomal RNA gene (SSU rRNA gene) from a particular protist from gill tissues of a significant fraction of the vesicomyid clams Calyptogena soyoae and C. okutanii complex and of the mussel Bathymodiolus platifrons and B. japonicus, all of which harbor chemosynthetic endosymbiont bacteria and dominate methane seeps in Sagami Bay, Japan. Based on the phylogeny of SSU rRNA gene, the organism in question was shown to belong to Alveolata. It is noteworthy that this protist did not affiliate with any known alveolate group, although being deeply branched within the lineage of Syndiniales, for which the monophyly was constantly recovered, but not robustly supported. In addition, the protist detected using PCR followed by sequencing was localized within gill epithelial cells of B. platifrons with whole‐mount fluorescence in situ hybridization. This protist may be an endoparasite or an endocommensal of Calyptogena spp. and Bathymodiolus spp., and possibly have physiological and ecological impacts on these bivalves. 相似文献
29.
Kiyotaka Chinzei 《Historical Biology》2013,25(2):223-231
In spite of their sessile nature, oysters of the genera Crassostrea, Ostrea and their allies are adapted to live on soft muddy bottoms. To provide them with secure attachment and to keep the animal above the surface of the mud, these soft-bottom oysters employ two basic strategies. They tend to be gregarious in their settlement, thereby providing one another with surfaces for attachment, and they form lightweight shells. In addition to these common characteristics, these oysters have followed different morphological pathways to live successfully on soft muddy bottoms. There are at least four types of morphologies: (1) relay-type succession (shells pile up on one another over many generations); (2) konbo-type elongation (both valves grow vertically upwards, the dorsal hinge remaining at the base, near the umbo); (3) cone-type elongation (the attached valve grows upwards and the free valve acts as a lid); and (4) lightweight recliners (bulky shells with lightweight fabrics and cavities within them). Judging from the variety of taxa that have adopted it and the sizes of their populations, the relay-type is the most successful of these strategies. Recliners were particularly common during the Mesozoic. The relay-type appeared in the Late Jurassic, becoming the dominant adaptive strategy during the Cenozoic. 相似文献
30.