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91.
92.
Ryuichi Sekioka Eriko Honjo Shugo Honda Hideyoshi Fuji Hiroki Akashiba Yasuyuki Mitani Shingo Yamasaki 《Bioorganic & medicinal chemistry》2018,26(2):435-442
Gamma-secretase modulators (GSMs) selectively inhibit the production of amyloid-β 42 (Aβ42) and may therefore be useful in the management of Alzheimer’s disease. Most heterocyclic GSMs that are not derived from nonsteroidal anti-inflammatory drugs contain an arylimidazole moiety that potentially inhibits cytochrome P450 (CYP) activity. Here, we discovered imidazopyridine derivatives that represent a new class of scaffold for GSMs, which do not have a strongly basic end group such as arylimidazole. High-throughput screening identified 2-methyl-8-[(2-methylbenzyl)oxy]-3-(pyridin-4-yl)imidazo[1,2-a]pyridine (3a), which inhibited the cellular production of Aβ42 (IC50?=?7.1?µM) without changing total production of Aβ. Structural optimization of this series of compounds identified 5-[8-(benzyloxy)-2-methylimidazo[1,2-a]pyridin-3-yl]-2-ethylisoindolin-1-one (3m) as a potent inhibitor of Aβ42 (IC50?=?0.39?µM) but not CYP3A4. Further, 3m demonstrated a sustained pharmacokinetic profile in mice and sufficiently penetrated the brain. 相似文献
93.
Experimental approaches to color pattern formation of lepidopteran insects have been made exclusively by analyzing pattern alterations in adult wings induced by operations. We microcauterized the presumptive black region of the dorsal forewing of the butterfly Pieris rapae and analyzed not only the resultant color pattern in the adult wing but also the cell behavior in the pupal wing epidermis around the injury. Cautery induced color alterations were as follows: (i) cautery up to 49.5 h after pupation resulted in white regions appearing within the black region while later cauteries induced larger white regions; (ii) cautery between 50 and 59.5 h resulted in the white regions induced by the cauteries being dramatically decreased; (iii) cautery after 60 h resulted in white regions that had almost disappeared. The examination of the cell behavior in the pupal wing epidermis after cauteries showed that the row formation of scale precursor cells was delayed. This delayed area varied with the time of cautery, in the same manner as that in the induced white area in the adult wing ((i) – (iii) above). The relationship between scale color alteration and the developmental delay of the scale row formation is discussed. 相似文献
94.
Motoki Higa Yuichi Yamaura Masayuki Senzaki Itsuro Koizumi Takeshi Takenaka Yoshiyuki Masatomi Kunikazu Momose 《Biodiversity and Conservation》2016,25(10):1829-1841
Charismatic megafauna have been used as icons and financial drivers of conservation efforts worldwide given that they are useful surrogates for biodiversity in general. However, tests of this premise have been constrained by data limitations, especially at large scales. Here we overcome this problem by combining large-scale citizen-sourced data with intensive expert observations of two endangered charismatic species, Blakiston’s fish owl (forest specialist) and the red-crowned crane (wetland specialist). We constructed large-scale maps of species richness for 52 forest and 23 grassland/wetland bird species using hierarchical community modeling and citizen-sourced data at 1, 2, 5, and 10-km grid resolutions. We compared the species richness of forest and grassland/wetland birds between the breeding and non-breeding sites of the two charismatic birds at each of the four spatial resolutions, and then assessed the scale dependency of the biodiversity surrogates. Regardless of the habitat amounts, owl and crane breeding sites had higher forest and grassland/wetland bird species richness, respectively. However, this surrogacy was more effective at finer scales (1–2-km resolutions), which corresponds to the charismatic species’ home range sizes (up to 9.4 ± 2.0 km2 for fish owls, and 3–4 km2 for cranes). Species richness showed the highest spatial variations at 1–2-km resolutions. We suggest that the agreement of functional scales between surrogate species and broader biodiversity is essential for successful surrogacy, and that habitat conservation and restoration targeting multiple charismatic species with different specialties can complement to biodiversity conservation. 相似文献
95.
96.
Muneo Yamada Shinya Suzu Eriko Akaiwa Noriko Wakimoto Kiyohiko Hatake Kazuo Motoyoshi Seiichi Shimamura 《Journal of cellular physiology》1997,173(1):1-9
The ability of purified human macrophage colony-stimulating factor (M-CSF) to accelerate the formation of stromal cells from murine bone marrow cells was investigated. The liquid culture of the marrow cells with M-CSF resulted in the formation of monolayers of macrophages on day 7. When the M-CSF was removed on that day and the residual adherent cells were cultured in the absence of M-CSF for an additional 7 days, many colonies appeared with cells that were morphologically distinguishable from M-CSF-derived macrophages. The appearance of the colonies was dependent on the concentration of M-CSF used at the beginning of the culture. Each colony was isolated as a single clone and analyzed. All clones were negative for esterase staining. These cells did not express M-CSF receptor mRNA and did not show a mitogenic response to M-CSF. On the contrary, these cells could be stimulated to proliferate by fibroblast growth factor and platelet-derived growth factor. The polymerase chain reaction analysis of these cells demonstrated constitutive expression of mRNA for M-CSF, stem cell factor, and interleukin (IL)-1, but not IL-3. Some clones expressed mRNA for granulocyte/M-CSF and IL-6. We also examined the ability of the cells to maintain murine bone marrow high proliferative potential colony-forming cells (HPP-CFC) in a coculture system. Most of the clones showed a significant increase in total HPP-CFC numbers after 2 weeks of coculture, although the extent of stimulation differed among clones. These results suggested that the colonies established by M-CSF were composed of functional stromal cells that were phenotypically different from macrophages. J. Cell. Physiol. 173:1–9, 1997. © 1997 Wiley-Liss, Inc. 相似文献
97.
Yoshikazu Watanabe Kohei Hayashida Daisuke Saito Toshihiro Takahashi Junichi Sakai Eriko Nakata Takashi Kanda Takashi Iwai Shigeto Hirayama Hideaki Fujii Tomio Yamakawa Hiroshi Nagase 《Bioorganic & medicinal chemistry letters》2017,27(15):3495-3498
We designed and synthesized novel δ opioid receptor (DOR) agonists 3a–i with an azatricyclodecane skeleton, which was a novel structural class of DOR agonists. Among them, 3b exhibited high values of binding affinity and potent agonistic activity for the DOR that were approximately equivalent to those of 2 which bore an oxazatricyclodecane skeleton. In vitro assays using the blood-brain barrier (BBB) permeability test kit supported the idea that 3b achieved an excellent BBB permeability by converting an oxygen atom of 2 to a carbon atom (methylene group) in the core skeleton. As a result, 3b showed potent antinociceptive effects. 相似文献
98.
Using a combination of atomic force, scanning and transmission electron microscopy, we found that avian erythrocytes infected with the avian malaria parasite Plasmodium gallinaceum develop 60 nm wide and 430 nm long furrow-like structures on the surface. Furrows begin to appear during the early trophozoite stage of the parasite’s development. They remain constant in size and density during the course of parasite maturation and are uniformly distributed in random orientations over the erythrocyte surface. In addition, the density of furrows is directly proportional to the number of parasites contained within the erythrocyte. These findings suggest that parasite-induced intraerythrocytic processes are involved in modifying the surface of host erythrocytes. These processes may be analogous to those of the human malaria parasite P. falciparum, which induces knob-like protrusions that mediate the pathogenic adherence of parasitized erythrocytes to microvessels. Although P. gallinaceum-infected erythrocytes do not seem to adhere to microvessels in the host chicken, the furrows might be involved in the pathogenesis of P. gallinaceum infections by some other mechanism involving host-pathogen interactions. 相似文献
99.
Fumihiro Fujiki Yoshihiro Oka Mai Kawakatsu Akihiro Tsuboi Hiroko Nakajima Olga A. Elisseeva Yukie Harada Zheyu Li Naoko Tatsumi Eriko Kamino Toshiaki Shirakata Sumiyuki Nishida Yuki Taniguchi Ichiro Kawase Yusuke Oji Haruo Sugiyama 《Microbiology and immunology》2008,52(12):591-600
The Wilms' tumor gene WT1 is overexpressed in various tumors, and the WT1 protein has been demonstrated to be an attractive target antigen for cancer immunotherapy. A WT1 protein‐derived 16‐mer peptide, WT1332 (KRYFKLSHLQMHSRKH), which was naturally generated through processing in cells and could elicit Th1‐type CD4+ helper T cell responses with an HLA‐DRB1*0405‐restriction has previously been identified by us. In the present study, it has been demonstrated that WT1332 can induce WT1332‐specific CD4+ T cell responses with the restriction of not only HLA‐DRB1*0405 but also HLA‐DRB1*1501, ‐DRB1*1502, or ‐DPB1*0901. These HLA class II‐restricted WT1332‐specific CD4+ T cell lines produced IFN‐γ but neither IL‐4 nor IL‐10 with WT1332 stimulation, thus showing a Th1‐type cytokine profile. Furthermore, HLA‐DRB1*1501 or ‐DRB1*1502‐restricted WT1332‐specific CD4+ T cell lines responded to WT1‐expressing transformed cells in an HLA‐DRB1‐restricted manner, which is consistent with our previous finding that WT1332 is a naturally processed peptide. These results indicate that the natural peptide, WT1332, is a promiscuous WT1‐specific helper epitope. WT1332 is expected to apply to cancer patients with various types of HLA class II as a WT1‐specific helper peptide in combination with HLA class I‐restricted WT1 peptides. 相似文献
100.
Murata T Suzuki E Ito S Sawatsubashi S Zhao Y Yamagata K Tanabe M Fujiyama S Kimura S Ueda T Matsukawa H Kouzmenko A Furutani T Kuranaga E Miura M Takeyama K Kato S 《Bioscience, biotechnology, and biochemistry》2008,72(9):2255-2261
Abnormal polyglutamine (polyQ) expansion in the N-terminal domain of the human androgen receptor (hAR) is known to cause spinobulbar muscular atrophy (SBMA), a hereditary human neurodegenerative disorder. To explore the molecular mechanisms of neurodegeneration in SBMA, we genetically screened modulators of neurodegeneration in a Drosophila SBMA experimental model system. We identified hoip as an accelerator of polyQ-induced neurodegeneration. We found that hoip forms a complex with 18s rRNA together nop56 and nop5 proteins, whose human homologs are known to form a snoRNP complex involved in ribosomal RNA processing. Significantly, the levels of mutant polyQ-hAR were up-regulated in a mutant line overexpressing hoip. Consistently, severe neurodegeneration phenotype (rough eye) was also observed in both nop56 and nop5 overexpression mutant lines. These findings suggest that the process of neurodegeneration induced by abnormal polyQ expansion in the hAR may be regulated by the activity of snoRNP complex. 相似文献