全文获取类型
收费全文 | 602篇 |
免费 | 37篇 |
专业分类
639篇 |
出版年
2023年 | 2篇 |
2022年 | 7篇 |
2021年 | 10篇 |
2020年 | 11篇 |
2019年 | 8篇 |
2018年 | 7篇 |
2017年 | 10篇 |
2016年 | 12篇 |
2015年 | 15篇 |
2014年 | 29篇 |
2013年 | 50篇 |
2012年 | 37篇 |
2011年 | 31篇 |
2010年 | 23篇 |
2009年 | 26篇 |
2008年 | 28篇 |
2007年 | 45篇 |
2006年 | 32篇 |
2005年 | 36篇 |
2004年 | 42篇 |
2003年 | 30篇 |
2002年 | 35篇 |
2001年 | 4篇 |
2000年 | 3篇 |
1999年 | 11篇 |
1998年 | 8篇 |
1997年 | 5篇 |
1996年 | 7篇 |
1995年 | 2篇 |
1994年 | 3篇 |
1993年 | 5篇 |
1992年 | 7篇 |
1991年 | 7篇 |
1990年 | 3篇 |
1989年 | 2篇 |
1987年 | 2篇 |
1986年 | 5篇 |
1985年 | 3篇 |
1984年 | 2篇 |
1983年 | 3篇 |
1982年 | 4篇 |
1981年 | 2篇 |
1980年 | 3篇 |
1979年 | 2篇 |
1974年 | 4篇 |
1972年 | 3篇 |
1967年 | 2篇 |
1925年 | 1篇 |
1923年 | 2篇 |
1919年 | 1篇 |
排序方式: 共有639条查询结果,搜索用时 15 毫秒
101.
Yukio Hirayama Mamiko Yoshimura Yuriko Ozeki Isamu Sugawara Tadashi Udagawa Satoru Mizuno Naoki Itano Koji Kimata Aki Tamaru Hisashi Ogura Kazuo Kobayashi Sohkichi Matsumoto 《PLoS pathogens》2009,5(10)
In spite of the importance of hyaluronan in host protection against infectious organisms in the alveolar spaces, its role in mycobacterial infection is unknown. In a previous study, we found that mycobacteria interact with hyaluronan on lung epithelial cells. Here, we have analyzed the role of hyaluronan after mycobacterial infection was established and found that pathogenic mycobacteria can grow by utilizing hyaluronan as a carbon source. Both mouse and human possess 3 kinds of hyaluronan synthases (HAS), designated HAS1, HAS2, and HAS3. Utilizing individual HAS-transfected cells, we show that HAS1 and HAS3 but not HAS2 support growth of mycobacteria. We found that the major hyaluronan synthase expressed in the lung is HAS1, and that its expression was increased after infection with Mycobacterium tuberculosis. Histochemical analysis demonstrated that hyaluronan profoundly accumulated in the granulomatous legion of the lungs in M. tuberculosis-infected mice and rhesus monkeys that died from tuberculosis. We detected hyaluronidase activity in the lysate of mycobacteria and showed that it was critical for hyaluronan-dependent extracellular growth. Finally, we showed that L-Ascorbic acid 6-hexadecanoate, a hyaluronidase inhibitor, suppressed growth of mycobacteria in vivo. Taken together, our data show that pathogenic mycobacteria exploit an intrinsic host-protective molecule, hyaluronan, to grow in the respiratory tract and demonstrate the potential usefulness of hyaluronidase inhibitors against mycobacterial diseases. 相似文献
102.
103.
Ariyasinghe A Morshed SR Mannoor MK Bakir HY Kawamura H Miyaji C Nagura T Kawamura T Watanabe H Sekikawa H Abo T 《The Journal of parasitology》2006,92(3):531-538
Mice were fed ad libitum with a normal diet (25% protein) or low-protein diets (0-12.5% protein) for a wk and then infected with a nonlethal or lethal strain of Plasmodium yoelii, that is, blood stage infection. The same diet was continued until recovery. Mice fed with a normal diet showed severe parasitemia during nonlethal infection, but survived the infection. They died within 2 wk in the case of lethal infection. However, all mice fed with low-protein diets survived without apparent parasitemia (there were small peaks of parasitemia) in cases of both nonlethal and lethal strains. These surviving mice were found to have acquired potent innate immunity, showing the expansion of NK1.1 -TCRint cells and the production of autoantibodies during malarial infection. Severe combined immunodeficiency (scid) mice, which lack TCRint cells as well as TCRhigh cells, did not survive after malarial infection of lethal strain of P. yoelii, even when low-protein diets were given. These results suggest that low-protein diets enhanced innate immunity and inversely decreased conventional immunity, and that these immunological deviations rendered mice resistant against malaria. The present outcome also reminds us of our experience in the field study of malaria, in which some inhabitants eventually avoided contracting malaria even after apparent malarial infection. 相似文献
104.
Chikako Nagasato Naoko Kajimura Makoto Terauchi Yoshinobu Mineyuki Taizo Motomura 《Protoplasma》2014,251(6):1347-1357
In brown algae, membrane resources for the new cell partition during cytokinesis are mainly flat cisternae (FCs) and Golgi-derived vesicles. We used electron tomography coupled with rapid freezing/freeze substitution of zygotes to clarify the structure of transient membrane compartments during cytokinesis in Silvetia zygotes. After mitosis, an amorphous membranous structure, considered to be an FC intermediate was observed near endoplasmic reticulum clusters, lying between two daughter nuclei. FCs were arrayed at the cytokinetic plane, and a tubular membranous network was formed around them. This network might be formed by the consecutive fusion of spherical vesicles that are linked to the edges of FCs to form a membranous network (MN). At the initial stage of the formation of a membranous sac (MS) from the MN, the MS had flat and swollen parts, with the latter showing membranous tunnels. Coated pits were detected with high frequency at the swollen parts of the MS. This observation indicated that membranous tunnels disappeared by recycling of excess membrane via endocytosis, and the swollen part became flat. The MN appeared at the edges of the growing MS. MN and the MN-MS complex were observed along the cytokinetic plane in several spaces. The MS expanded by the incorporation of MN or other MS in its neighborhood. With the maturation of the new cell partition membrane, the thickness of the MS became constant and the membrane cavity disappeared. The changes in the surface area and volume of the transient membrane compartment during cytokinesis were analyzed from the tomographic data. 相似文献
105.
T. Y. C. Massuda L. A. Nagashima P. C. Leonello M. S. Kaminami M. S. Mantovani A. Sano J. Uno E. J. Venancio Z. P. Camargo E. N. Itano 《Mycopathologia》2011,171(3):161-169
Paracoccidioidomycosis (PCM) is a systemic mycosis caused by the fungus Paracoccidioides brasiliensis (Pb). The cyclosporin A (CsA) is an immunosuppressant drug that inhibits calcineurin and has been described as a potential
antifungal drug. The present study investigated the effect of CsA on the immune response, fungal load/antigenemia in experimental
murine PCM. It was used four groups of BALB/c mice: (a) infected with 1 × 105 Pb18 yeast cells (Pb), (b) infected and treated with CsA every other day 10 mg/kg of CsA (s.c.) during 30 days (Pb/CsA),
(c) treated with CsA (CsA) and (d) no infected/treated (PBS). The immune response was evaluated by lymphocyte proliferation,
DTH assays to exoAgs, ELISA for IgG anti-gp43 (specific immune responses) and cytokine serum levels (IFN-γ, TNF-α, IL-4 and
IL-10). Fungal load was determined by lung colony-forming units (CFU) counts, lung and liver histopathology analysis and antigenemia
determined by inhibition-ELISA. As expected, CsA was able to inhibit the specific cellular and humoral immune response (P < 0.05), with decrease in serum IFN-γ, TNF-α and IL-4 levels (P < 0.05). Cyclosporin A treatment also resulted in significantly decreased lung Pb CFU (P < 0.05) as well as a lower number of yeasts in the lung and liver (P < 0.05) by histopathology. In concordance, the decreased antigenemia was observed in Pb/CsA group (P < 0.05). In conclusion, even with immunosuppressive action, treatment with CsA results in decreased lung fungal load/antigenemia
in experimental PCM in BALB/c mice. Further study is required to determine whether this represents less severe disease or
protection by CsA. 相似文献
106.
Matsunaga H Hokari R Ueda T Kurihara C Hozumi H Higashiyama M Okada Y Watanabe C Komoto S Nakamura M Kawaguchi A Nagao S Sekiyama A Miura S 《American journal of physiology. Gastrointestinal and liver physiology》2011,301(3):G555-G564
Psychological stress is an environmental factor considered to be a precipitating factor of inflammatory bowel disease. Interleukin (IL)-18 plays a role in stress-induced aggravation in some diseases. The aim of this study was to establish a model of murine colitis exacerbated by psychological stress and to clarify the role of IL-18 in this model. Male C57Bl/6 mice and IL-18(-/-) mice were used for this study. The mice received dextran sulfate sodium (DSS) for induction of colitis. Some mice were exposed to psychological stress using a communication box. Body weight, colonic length, and histological inflammation were measured for assessment of colitis. Tumor necrosis factor (TNF)-α and IL-18 expression in the colon and IL-18 expression in the adrenal gland were analyzed using real-time PCR. The effect of anti-IL-18 antibody was also investigated. Effects of TNF-α and IL-18 on cytokine expressions were studied using the colonic epithelial cell line LS174T. Induction of psychological stress in DSS-treated wild-type mice significantly exacerbated colitis with enhanced expression of proinflammatory cytokines and IL-18. However, induction of psychological stress in DSS-treated IL-18(-/-) mice did not aggravate colitis compared with that in the IL-18(-/-) group given only DSS treatment. Stress-induced aggravation of colitis was ameliorated significantly by anti-IL-18 antibody treatment. IL-18 did not enhance TNF-α-induced expression of intercellular adhesion molecule-1 or IL-8 in LS174T. We established a model of colitis exacerbated by psychological stress. Psychological stress enhanced IL-18 expression and plays a proinflammatory role in stress-induced aggravation of colitis. 相似文献
107.
NMDA receptor regulates migration of newly generated neurons in the adult hippocampus via Disrupted-In-Schizophrenia 1 (DISC1) 总被引:1,自引:0,他引:1
Namba T Ming GL Song H Waga C Enomoto A Kaibuchi K Kohsaka S Uchino S 《Journal of neurochemistry》2011,118(1):34-44
In the mammalian brain, new neurons are continuously generated throughout life in the dentate gyrus (DG) of the hippocampus. Previous studies have established that newborn neurons migrate a short distance to be integrated into a pre-existing neuronal circuit in the hippocampus. How the migration of newborn neurons is governed by extracellular signals, however, has not been fully understood. Here, we report that NMDA receptor (NMDA-R)-mediated signaling is essential for the proper migration and positioning of newborn neurons in the DG. An intraperitoneal injection of the NMDA-R antagonists, memantine, or 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) into adult male mice caused the aberrant positioning of newborn neurons, resulting in the overextension of their migration in the DG. Interestingly, we revealed that the administration of NMDA-R antagonists leads to a decrease in the expression of Disrupted-In-Schizophrenia 1 (DISC1), a candidate susceptibility gene for major psychiatric disorders such as schizophrenia, which is also known as a critical regulator of neuronal migration in the DG. Furthermore, the overextended migration of newborn neurons induced by the NMDA-R antagonists was significantly rescued by exogenous expression of DISC1. Collectively, these results suggest that the NMDA-R signaling pathway governs the migration of newborn neurons via the regulation of DISC1 expression in the DG. 相似文献
108.
Furutani-Seiki M Sasado T Morinaga C Suwa H Niwa K Yoda H Deguchi T Hirose Y Yasuoka A Henrich T Watanabe T Iwanami N Kitagawa D Saito K Asaka S Osakada M Kunimatsu S Momoi A Elmasri H Winkler C Ramialison M Loosli F Quiring R Carl M Grabher C Winkler S Del Bene F Shinomiya A Kota Y Yamanaka T Okamoto Y Takahashi K Todo T Abe K Takahama Y Tanaka M Mitani H Katada T Nishina H Nakajima N Wittbrodt J Kondoh H 《Mechanisms of development》2004,121(7-8):647-658
A large-scale mutagenesis screen was performed in Medaka to identify genes acting in diverse developmental processes. Mutations were identified in homozygous F3 progeny derived from ENU-treated founder males. In addition to the morphological inspection of live embryos, other approaches were used to detect abnormalities in organogenesis and in specific cellular processes, including germ cell migration, nerve tract formation, sensory organ differentiation and DNA repair. Among 2031 embryonic lethal mutations identified, 312 causing defects in organogenesis were selected for further analyses. From these, 126 mutations were characterized genetically and assigned to 105 genes. The similarity of the development of Medaka and zebrafish facilitated the comparison of mutant phenotypes, which indicated that many mutations in Medaka cause unique phenotypes so far unrecorded in zebrafish. Even when mutations of the two fish species cause a similar phenotype such as one-eyed-pinhead or parachute, more genes were found in Medaka than in zebrafish that produced the same phenotype when mutated. These observations suggest that many Medaka mutants represent new genes and, therefore, are important complements to the collection of zebrafish mutants that have proven so valuable for exploring genomic function in development. 相似文献
109.
Yoda H Hirose Y Yasuoka A Sasado T Morinaga C Deguchi T Henrich T Iwanami N Watanabe T Osakada M Kunimatsu S Wittbrodt J Suwa H Niwa K Okamoto Y Yamanaka T Kondoh H Furutani-Seiki M 《Mechanisms of development》2004,121(7-8):715-728
We screened for mutations affecting retinotectal axonal projection in Medaka, Oryzias latipes. In wild-type Medaka embryos, all the axons of retinal ganglion cells (RGCs) project to the contralateral tectum, such that the topological relationship of the retinal field is maintained. We labeled RGC axons using DiI/DiO at the nasodorsal and temporoventral positions of the retina, and screened for mutations affecting the pattern of stereotypic projections to the tectum. By screening 184 mutagenized haploid genomes, seven mutations in five genes causing defects in axonal pathfinding were identified, whereas mutations affecting the topographic projection of RGC axons were not found. The mutants were grouped into two classes according to their phenotypes. In mutants of Class I, a subpopulation of the RGC axons branched out either immediately after leaving the eye or after reaching the midline, and this axonal subpopulation projected to the ipsilateral tectum. In mutants of Class II, subpopulations of RGC axons branched out after crossing the midline and projected aberrantly. These mutants will provide clues to understanding the functions of genes essential for axonal pathfinding, which may be conserved or partly divergent among vertebrates. 相似文献
110.
Sasado T Morinaga C Niwa K Shinomiya A Yasuoka A Suwa H Hirose Y Yoda H Henrich T Deguchi T Iwanami N Watanabe T Kunimatsu S Osakada M Okamoto Y Kota Y Yamanaka T Tanaka M Kondoh H Furutani-Seiki M 《Mechanisms of development》2004,121(7-8):817-828
The development of germ cells has been intensively studied in Medaka (Oryzias latipes). We have undertaken a large-scale screen to identify mutations affecting the development of primordial germ cells (PGCs) in Medaka. Embryos derived from mutagenized founder fish were screened for an abnormal distribution or number of PGCs at embryonic stage 27 by RNA in situ hybridization for the Medaka vasa homologue (olvas). At this stage, PGCs coalesce into two bilateral vasa-expressing foci in the ventrolateral regions of the trunk after their migration and group organization. Nineteen mutations were identified from a screen corresponding to 450 mutagenized haploid genomes. Eleven of the mutations caused altered PGC distribution. Most of these alterations were associated with morphological abnormalities and could be grouped into four phenotypic classes: Class 1, PGCs dispersed into bilateral lines; Class 2, PGCs dispersed in a region more medial than that in Class 1; Class 3, PGCs scattered laterally and over the yolk sac area; and Class 4, PGCs clustered in a single median focus. Eight mutations caused a decrease in the number of PGCs. This decrease was observed in the offspring of heterozygous mothers, indicating the contribution of a maternal factor in determining PGC abundance. Taken together, these mutations should prove useful in identifying molecular mechanisms underlying the early PGC development and migration. 相似文献