全文获取类型
收费全文 | 2474篇 |
免费 | 133篇 |
国内免费 | 3篇 |
专业分类
2610篇 |
出版年
2022年 | 6篇 |
2021年 | 17篇 |
2020年 | 9篇 |
2019年 | 26篇 |
2018年 | 25篇 |
2017年 | 27篇 |
2016年 | 44篇 |
2015年 | 50篇 |
2014年 | 75篇 |
2013年 | 222篇 |
2012年 | 131篇 |
2011年 | 119篇 |
2010年 | 82篇 |
2009年 | 99篇 |
2008年 | 154篇 |
2007年 | 142篇 |
2006年 | 147篇 |
2005年 | 139篇 |
2004年 | 161篇 |
2003年 | 141篇 |
2002年 | 151篇 |
2001年 | 31篇 |
2000年 | 26篇 |
1999年 | 34篇 |
1998年 | 43篇 |
1997年 | 35篇 |
1996年 | 25篇 |
1995年 | 43篇 |
1994年 | 31篇 |
1993年 | 40篇 |
1992年 | 28篇 |
1991年 | 29篇 |
1990年 | 24篇 |
1989年 | 23篇 |
1988年 | 24篇 |
1987年 | 14篇 |
1986年 | 14篇 |
1985年 | 13篇 |
1984年 | 18篇 |
1983年 | 13篇 |
1982年 | 15篇 |
1981年 | 15篇 |
1980年 | 10篇 |
1979年 | 7篇 |
1978年 | 6篇 |
1977年 | 11篇 |
1976年 | 15篇 |
1975年 | 12篇 |
1972年 | 6篇 |
1970年 | 8篇 |
排序方式: 共有2610条查询结果,搜索用时 0 毫秒
991.
Dendritic cell-based vaccines suppress metastatic liver tumor via activation of local innate and acquired immunity 总被引:2,自引:0,他引:2
Yamaguchi S Tatsumi T Takehara T Sasakawa A Hikita H Kohga K Uemura A Sakamori R Ohkawa K Hayashi N 《Cancer immunology, immunotherapy : CII》2008,57(12):1861-1869
Background Dendritic cell (DC)-based vaccines have been applied clinically in the setting of cancer, but tumor-associated antigens (TAAs)
have not yet been enough identified in various cancers. In this study, we investigated whether preventive vaccination with
unpulsed DCs or peptide-pulsed DCs could offer anti-tumor effects against MC38 or BL6 liver tumors.
Methods Mice were subcutaneously (s.c.) immunized with unpulsed DCs or the recently defined TAA EphA2 derived peptide-pulsed dendritic
cells (Eph-DCs) to treat EphA2-positive MC38 and EphA2-negative BL6 liver tumors. Liver mononuclear cells (LMNCs) from treated
mice were subjected to 51Cr release assays against YAC-1 target cells. In some experiments, mice were injected with anti-CD8, anti-CD4 or anti-asialo
GM1 antibody to deplete each lymphocyte subsets.
Results Immunization with unpulsed DCs displayed comparable efficacy against both MC38 and BL6 liver tumors when compared with Eph-DCs.
Both DC-based vaccines significantly augmented the cytotoxicity of LMNCs against YAC-1 cells. In vivo antibody depletion studies
revealed that NK cells, as well as, CD4+ and CD8+ T cells play critical roles in the anti-tumor efficacy associated with either
DC-based modality.
Tumor-specific cytotoxic T lymphocyte (CTL) activity was generally higher if mice had received Eph-DCs versus unpulsed DCs.
Importantly, the mice that had been protected from MC38 liver tumor by either unpulsed DCs or Eph-DCs became resistant to
s.c. MC38 rechallenge, but not to BL6 rechallenge.
Conclusions These results demonstrate that unpulsed DC vaccines might serve as an effective therapy for treating metastatic liver tumor, for which TAA has not yet been identified.
Shinjiro Yamaguchi and Tomohide Tatsumi contributed equally to this work. 相似文献
992.
Deguchi Y Toyoizumi T Masuda S Yasuhara A Mohri S Yamada M Inoue Y Kinae N 《Mutation research》2007,627(2):178-185
To develop a simple system for monitoring the presence of mutagens/carcinogens in the leachates from landfill sites, we used a micronucleus test and a single cell gel electrophoresis (comet) assay originally developed for mice and rats on goldfish (Carassius auratus). The goldfish were exposed for 9 days to the leachate with chemical and biological treatment (treated leachate) or without treatment (raw leachate). The goldfish exposed to several samples died because of the high concentrations of NaCl or ammonium ion (NH4+). In the comet assay using peripheral erythrocytes, the raw leachates showed higher mutagenic activity than the treated leachates. In the micronucleus test, it was difficult to detect the micronuclei in peripheral erythrocytes. On the other hand, the frequency of micronuclei was high in gill cells of goldfish exposed to the raw leachates compared to the treated leachates. A combination of the two bioassays was shown to be useful to evaluate the mutagenic activity of the leachates. We also propose a new scoring method for determination of water quality by using acute toxicity and mutagenic activity. 相似文献
993.
994.
Husain K Vazquez M Ansari RA Malafa MP Lalla J 《Molecular and cellular biochemistry》2008,307(1-2):51-58
The link between chronic alcohol consumption and cardiovascular injury including hypertension is well known. However, molecular
mediators implicated with alcohol-induced elevation in blood pressure (BP) remain elusive. The aim of this study was to investigate
the relationship of chronic ethanol-induced endothelial injury and elevation in BP with angiotensin II levels in rats. Male
Fisher rats were divided into two groups of seven animals each and treated as follows: (1) Control (5% sucrose, orally) daily
for 12 weeks and (2) ethanol (4 g kg−1, orally) daily for 12 weeks. The BP (systolic, diastolic, and mean) was recorded every week. The animals were anesthetized
with pentobarbital after 12 weeks; blood and thoracic aorta were isolated and analyzed for aortic reactivity response, angiotensin
II levels, and oxidative endothelial injury. The results show that the systolic, diastolic, and mean BP were significantly
elevated 12 weeks after ethanol ingestion. The increased BP was related to elevated angiotensin II levels in the plasma and
aorta of alcohol treated group compared to control. The aortic NADPH oxidase activity, ratio of oxidized to reduced glutathione
(GSSG/GSH) and lipid peroxidation significantly increased, whereas nitric oxide (NO), endothelial NO synthase (eNOS), and
vascular endothelial growth factor (VEGF) protein expressions were depressed in alcohol group compared to control. The phenylephrine-mediated
vasoconstriction response was not altered, while acetylcholine-mediated vasorelaxation response was depressed in the aorta
of ethanol treated rats compared to control. It is concluded that chronic ethanol ingestion induces hypertension which is
correlated with elevated tissue angiotensin II levels, activation of NADPH oxidase activity causing endothelial injury, depletion
of endothelial NO generating system, and impaired vascular relaxation in rats. 相似文献
995.
Horii-Hayashi N Okuda H Tatsumi K Ishizaka S Yoshikawa M Wanaka A 《Cell and tissue research》2008,334(2):163-177
Versican is a chondroitin sulfate proteoglycan belonging to the lectican family. Versican has two glycosaminoglycan attachment
regions, named the GAGα and GAGβ domains, which are both regulated by alternative splicing and yield four protein isoforms.
We have investigated the expression and localization of versican in the developing and adult brain by using anti-versican
GAGα and GAGβ antibodies. Western analysis revealed that GAGα-reactive isoform was dominant in the adult brain. Immunohistochemical
study demonstrated that GAGα immunoreactivity was detectable from neonatal periods to adulthood, whereas GAGβ immunoreactivity
completely disappeared within 3 weeks of birth. In the adult brain, GAGα immunoreactivity was seen in the white matter regions
and was also localized in the gray matter including somata and dendrites of cortical and hippocampal pyramidal neurons and
cerebellar Purkinje cells. In contrast, GAGα immunoreactivity was not localized on parvalbumin-positive interneurons and cerebellar
stellate cells. Furthermore, GAGα immunoreactivity was not co-localized with perineuronal net markers such as Wisteria floribunda agglutinin lectin and phosphacan. Thus, versican was localized on large projection neurons rather than small interneurons. To confirm
the binding mechanism of versican to neurons, hyaluronan and chondroitin sulfates were enzymatically removed from brain sections
before the immunolabeling of versican. These treatments had no effect on the labeling pattern of versican, suggesting that
other versican-interactive molecules are involved in the binding of versican to neurons.
This study was supported by a Grant-in-Aid for Scientific Research on Priority Areas “Advanced Brain Science Project” from
the Ministry of Education, Culture, Sports, Science, and Technology, Japan. 相似文献
996.
997.
Novel and potent inhibitors of 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) were identified based on oxazolidinedione and thiazolidinedione derivatives, starting from a high-throughput screening hit, 5-(3-bromo-4-hydroxybenzyl)-3-(4-methoxyphenyl)-1,3-thiazol-2-one. 5-(3-Bromo-4-hydroxybenzylidene)-3-(4-methoxyphenyl)-2-thioxo-1,3-thiazolidin-4-one exhibited a promising activity profile and demonstrated significant selectivity over the related 17β-HSD isoenzymes and nuclear receptors. 相似文献
998.
Kazuya Imazu Shotaro Tanaka Akio Kuroda Yuki Anbe Junichi Kato Hisao Ohtake 《Applied microbiology》1998,64(10):3754-3758
Klebsiella aerogenes ATCC 9621 was able to utilize phosphonates (Pn), including aminoethylphosphonate, ethylphosphonate, methylphosphonate (MPn), and phosphonoacetate, and inorganic phosphite (Pt) as sole sources of phosphorus (P). The products of the phn gene cluster were absolutely required for Pn breakdown and Pt oxidation to inorganic phosphate (Pi) in this organism. To determine if K. aerogenes ATCC 9621 could be engineered to enhance the utilization of Pn and Pt, a multicopy plasmid, pBI05, which carried the entire phn gene cluster, was introduced into this strain. Despite the increased dosage of the phn genes, K. aerogenes ATCC 9621(pBI05) could utilize only up to 1.1-fold more Pn and Pt than did the control strain with the parent vector alone. These results suggested that Pi, which was generated from Pn and Pt, might limit further utilization of these P compounds. Consequently, to convert the resulting Pi to polyphosphate (polyP), the plasmid pKP28, which carried the K. aerogenes ppk gene (which encodes polyP kinase), was introduced into K. aerogenes ATCC 9621(pBI05). Overexpression of the ppk gene in K. aerogenes ATCC 9621(pBI05, pKP28) resulted in a 2.5-fold increase in Pt utilization over that of the control strain. This recombinant strain also accumulated approximately sixfold more P than did the control strain when the cells were grown with MPn as a sole source of P. 相似文献
999.
Akio Kitao 《Proteins》2013,81(6):1005-1016
We propose a fast clustering and reranking method, CyClus, for protein–protein docking decoys. This method enables comprehensive clustering of whole decoys generated by rigid‐body docking using cylindrical approximation of the protein–proteininterface and hierarchical clustering procedures. We demonstrate the clustering and reranking of 54,000 decoy structures generated by ZDOCK for each complex within a few minutes. After parameter tuning for the test set in ZDOCK benchmark 2.0 with the ZDOCK and ZRANK scoring functions, blind tests for the incremental data in ZDOCK benchmark 3.0 and 4.0 were conducted. CyClus successfully generated smaller subsets of decoys containing near‐native decoys. For example, the number of decoys required to create subsets containing near‐native decoys with 80% probability was reduced from 22% to 50% of the number required in the original ZDOCK. Although specific ZDOCK and ZRANK results were demonstrated, the CyClus algorithm was designed to be more general and can be applied to a wide range of decoys and scoring functions by adjusting just two parameters, p and T. CyClus results were also compared to those from ClusPro. Proteins 2013; © 2012 Wiley Periodicals, Inc. 相似文献
1000.
Matsumoto H Hirata Y Otsuka K Iwata T Inazumi A Niimi A Ito I Ogawa E Muro S Sakai H Chin K Oku Y Mishima M 《Cytokine》2012,57(1):19-24
Physiological mechanisms associated with interleukin-13 (IL-13), a key cytokine in asthma, in intracellular Ca2+ signaling in airway smooth muscle cells (ASMCs) remain unclear. The aim of this study was to assess effects of IL-13 on Ca2+ oscillations in response to leukotriene D4 (LTD4) in human cultured ASMCs.LTD4-induced Ca2+ oscillations in ASMCs pretreated with IL-13 were imaged by confocal microscopy. mRNA expressions of cysteinyl leukotriene 1 receptors (CysLT1R), CD38, involved with the ryanodine receptors (RyR) system, and transient receptor potential canonical (TRPC), involved with store-operated Ca2+ entry (SOCE), were determined by real-time PCR. In IL-13-pretreated ASMCs, frequency of LTD4-induced Ca2+ oscillations and number of oscillating cells were significantly increased compared with untreated ASMCs. Both xestospongin C, a specific inhibitor of inositol 1,4,5-triphosphate receptors (IP3R), and ryanodine or ruthenium red, inhibitors of RyR, partially blocked LTD4-induced Ca2+ oscillations. Ca2+ oscillations were almost completely inhibited by 50 μM of 2-aminoethoxydiphenyl borate (2-APB), which dominantly blocks SOCE but not IP3R at this concentration. Pretreatment with IL-13 increased the mRNA expressions of CysLT1R and CD38, but not of TRPC1 and TRPC3.We conclude that IL-13 enhances frequency of LTD4-induced Ca2+ oscillations in human ASMCs, which may be cooperatively modulated by IP3R, RyR systems and possibly by SOCE. 相似文献