全文获取类型
收费全文 | 2890篇 |
免费 | 154篇 |
出版年
2023年 | 6篇 |
2022年 | 15篇 |
2021年 | 39篇 |
2020年 | 17篇 |
2019年 | 30篇 |
2018年 | 49篇 |
2017年 | 26篇 |
2016年 | 55篇 |
2015年 | 85篇 |
2014年 | 106篇 |
2013年 | 185篇 |
2012年 | 230篇 |
2011年 | 210篇 |
2010年 | 128篇 |
2009年 | 109篇 |
2008年 | 202篇 |
2007年 | 207篇 |
2006年 | 185篇 |
2005年 | 172篇 |
2004年 | 203篇 |
2003年 | 169篇 |
2002年 | 197篇 |
2001年 | 20篇 |
2000年 | 24篇 |
1999年 | 26篇 |
1998年 | 31篇 |
1997年 | 33篇 |
1996年 | 38篇 |
1995年 | 29篇 |
1994年 | 30篇 |
1993年 | 25篇 |
1992年 | 16篇 |
1991年 | 21篇 |
1990年 | 14篇 |
1989年 | 14篇 |
1988年 | 13篇 |
1987年 | 13篇 |
1986年 | 7篇 |
1985年 | 3篇 |
1984年 | 3篇 |
1983年 | 10篇 |
1982年 | 9篇 |
1981年 | 9篇 |
1980年 | 10篇 |
1979年 | 6篇 |
1976年 | 2篇 |
1975年 | 2篇 |
1974年 | 4篇 |
1970年 | 2篇 |
1969年 | 2篇 |
排序方式: 共有3044条查询结果,搜索用时 46 毫秒
71.
To clarify changes of neutrophil functions, mental conditions and relationships among them, 19 male elite long‐distance runners participated in this study for 6 months. Examinations, with informed consent, were carried out once a month. According to the results of physical characteristics, it was thought that training intensity was reduced after the main race, Hakone‐Ekiden. Neutrophil functions were estimated by indices of reactive oxygen species production, determined by luminol‐ and lucigenin‐dependent chemiluminescence (LmCL and LgCL, respectively) and cytochrome c reduction methods. The peak times (PT) in LmCL and LgCL (LgPT) were most prolonged in January and December, respectively. The peak heights (PH) in LmCL (LmPH) were enhanced in February. Decreased levels of negative categories in the profile of mood state (POMS) questionnaire and the total mood state (TMS) of POMS were observed in February without significance. Correlation analysis using measured values revealed significant negative correlation between LmPH and negative categories in POMS; however, these correlations were possibly a mere appearance, caused by personal differences. After eliminating personal differences, LgPT correlated positively to depression (p < 0.05), anger (p < 0.05), fatigue (p < 0.01) and TMS (p < 0.05). These results suggest that the mean time from the recognition of foreign matter to the maximum production of superoxide from neutrophils is prolonged in the mentally suppressed conditions found under continuous physical training. Copyright © 2012 John Wiley & Sons, Ltd. 相似文献
72.
Hiroyuki Hayakawa Hiromichi Tanaka Kazuhiro Haraguchi Masami Mayumi Masako Nakajima Takashi Sakamaki 《Nucleosides, nucleotides & nucleic acids》2013,32(1):121-128
Abstract Chlorination of purine nucleosides protected with tert-butyldimethylsilyl (TBDMS) group was examined by the reaction of the C-8 lithiated species, generated by LDA, with p-toluenesulfonyl chloride as an electrophile. This provides a new method for the preparation of 8-chloropurine nucleosides. 相似文献
73.
Yoshikazu Arai Jun Ohgane Shuh‐hei Fujishiro Kazuaki Nakano Hitomi Matsunari Masahito Watanabe Kazuhiro Umeyama Dai Azuma Naomi Uchida Nozomu Sakamoto Tomohiro Makino Shintaro Yagi Kunio Shiota Yutaka Hanazono Hiroshi Nagashima 《Genesis (New York, N.Y. : 2000)》2013,51(11):763-776
Porcine induced pluripotent stem cells (iPSCs) provide useful information for translational research. The quality of iPSCs can be assessed by their ability to differentiate into various cell types after chimera formation. However, analysis of chimera formation in pigs is a labor‐intensive and costly process, necessitating a simple evaluation method for porcine iPSCs. Our previous study identified mouse embryonic stem cell (ESC)‐specific hypomethylated loci (EShypo‐T‐DMRs), and, in this study, 36 genes selected from these were used to evaluate porcine iPSC lines. Based on the methylation profiles of the 36 genes, the iPSC line, Porco Rosso‐4, was found closest to mouse pluripotent stem cells among 5 porcine iPSCs. Moreover, Porco Rosso‐4 more efficiently contributed to the inner cell mass (ICM) of blastocysts than the iPSC line showing the lowest reprogramming of the 36 genes (Porco Rosso‐622‐14), indicating that the DNA methylation profile correlates with efficiency of ICM contribution. Furthermore, factors known to enhance iPSC quality (serum‐free medium with PD0325901 and CHIR99021) improved the methylation status at the 36 genes. Thus, the DNA methylation profile of these 36 genes is a viable index for evaluation of porcine iPSCs. genesis 51:763–776. © 2013 Wiley Periodicals, Inc. 相似文献
74.
The sirtuins are members of the NAD+-dependent histone deacetylase family that contribute to various cellular functions that affect aging, disease, and cancer development in metazoans. However, the physiological roles of the fungus-specific sirtuin family are still poorly understood. Here, we determined a novel function of the fungus-specific sirtuin HstD/Aspergillus oryzae Hst4 (AoHst4), which is a homolog of Hst4 in A. oryzae yeast. The deletion of all histone deacetylases in A. oryzae demonstrated that the fungus-specific sirtuin HstD/AoHst4 is required for the coordination of fungal development and secondary metabolite production. We also show that the expression of the laeA gene, which is the most studied fungus-specific coordinator for the regulation of secondary metabolism and fungal development, was induced in a ΔhstD strain. Genetic interaction analysis of hstD/Aohst4 and laeA clearly indicated that HstD/AoHst4 works upstream of LaeA to coordinate secondary metabolism and fungal development. The hstD/Aohst4 and laeA genes are fungus specific but conserved in the vast family of filamentous fungi. Thus, we conclude that the fungus-specific sirtuin HstD/AoHst4 coordinates fungal development and secondary metabolism via the regulation of LaeA in filamentous fungi. 相似文献
75.
Kazuhiro Shiizaki Masanobu Kawanishi Takashi Yagi 《Mutation Research - Genetic Toxicology and Environmental Mutagenesis》2013,750(1-2):77-85
Benzo[a]pyrene (BaP) is metabolically activated by cytochrome P450 enzymes, and forms DNA adduct leading to mutations. Cytochrome P450 1A1 plays a central role in this activation step, and this enzyme is strongly induced by chemical agents that bind to the aryl hydrocarbon receptor (AhR), which is also known as a dioxin receptor. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a potent AhR ligand has not been shown to form any DNA adduct, but has a possibility to aggravate the toxicity of precarcinogenic polycyclic hydrocarbons through the induction of metabolic enzymes. We treated human hepatoma cells (HepG2) with TCDD, and subsequently exposed them to BaP to elucidate the synergistic effects on mutations. Surprisingly, mutant frequency induced by BaP at the hypoxanthine-guanine phosphribosyltransferase (HPRT) locus was decreased by pretreatment with TCDD. In correlation with decrease in the mutant frequencies, BaP–DNA adduct formation was also decreased by TCDD pretreatment. This suppressive effect of TCDD was more potent when the cells were exposed to (±)-anti-benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE), a reactive metabolic intermediate of BaP. Among the enzymes catalyzing BaP oxidation and conjugation, cytochrome P450 1A1, 1A2, 3A4 and UDP-glucuronosyltransferase 1A1 mRNAs were induced by the exposure to TCDD. In cytochrome P450 1A1-deficient murine cells and cytochrome P450 1A1-uninducible human cells, TCDD could not suppress BPDE–DNA adduct formation. Further experiments using “Tet-On” cytochrome P450 1A1-overexpressing cells and a recombinant cytochrome P450 1A1 enzyme demonstrated that this is the key enzyme involved in the biotransformation of BaP, that is, both production and inactivation of BPDE. We conclude that TCDD-induced cytochrome P450 catalyzes the metabolism of BPDE to as yet-unidentified products that are not apparently DNA-reactive, thereby reducing mutations in hepatoma cells. 相似文献
76.
Takamichi Izumi Makoto Kondo Takuya Takahashi Nao Fujieda Atsushi Kondo Naohisa Tamura Tomohiro Murakawa Jun Nakajima Hirokazu Matsushita Kazuhiro Kakimi 《Cytotherapy》2013,15(4):481-491
Background aimsAdoptive immunotherapy is emerging as a potent anti-tumor treatment modality; Vγ9Vδ2 T cells may represent appropriate agents for such cancer immunotherapy. To improve the currently limited success of Vγ9Vδ2 T-cell–based immunotherapy, we examined the in vivo dynamics of these adoptively-transferred cells and hypothesized that interleukin (IL)-15 is the potential factor for Vγ9δ2 T cell in vivo survival.MethodsWe conducted a clinical trial of adoptive Vγ9Vδ2 T-cell transfer therapy in six colorectal cancer patients who received pulmonary metastasectomy. Patients' peripheral blood mononuclear cells were stimulated with zoledronate (5 μmol/L) and IL-2 (1000 IU/mL) for 14 d. Harvested cells, mostly Vγ9Vδ2 T cells, were given intravenously weekly without additional IL-2 eight times in total. The frequency, phenotype and common γ-chain cytokine receptor expression of Vγ9Vδ2 T cells in peripheral blood was monitored by flow cytometry at each time point during treatment and 4 and 12 weeks after the last administration.ResultsAdoptively transferred Vγ9Vδ2 T cells expanded well without exogenous IL-2 administration or lymphodepleting preconditioning. They maintained effector functions in terms of interferon-γ secretion and prompt release of cytotoxic granules in response to PMA/ionomycin or isopentenyl pyrophosphate–positive cells. Because they are IL-2Rα?IL-7Rα?IL-15Rα?IL-2Rβ+γc+, it is likely that IL-2 or IL-15 is required for their maintenance.ConclusionsThe persistence of large numbers of functionally active adoptively transferred Vγ9Vδ2 T cells in the absence of exogenous IL-2 implies that an endogenous factor, such as IL-15 transpresentation, is adequate to support these cells in vivo. 相似文献
77.
Yasuhito Hamaguchi Manabu Fujimoto Takashi Matsushita Kenzo Kaji Kazuhiro Komura Minoru Hasegawa Masanari Kodera Eiji Muroi Keita Fujikawa Mariko Seishima Hidehiro Yamada Ryo Yamada Shinichi Sato Kazuhiko Takehara Masataka Kuwana 《PloS one》2013,8(4)
Objective
To identify similarities and differences in the clinical features of adult Japanese patients with individual anti-aminoacyl-tRNA synthetase antibodies (anti-ARS Abs).Methods
This was a retrospective analysis of 166 adult Japanese patients with anti-ARS Abs detected by immunoprecipitation assays. These patients had visited Kanazawa University Hospital or collaborating medical centers from 2003 to 2009.Results
Anti-ARS Ab specificity included anti-Jo-1 (36%), anti-EJ (23%), anti-PL-7 (18%), anti-PL-12 (11%), anti-KS (8%), and anti-OJ (5%). These anti-ARS Abs were mutually exclusive, except for one serum Ab that had both anti-PL-7 and PL-12 reactivity. Myositis was closely associated with anti-Jo-1, anti-EJ, and anti-PL-7, while interstitial lung disease (ILD) was correlated with all 6 anti-ARS Abs. Dermatomyositis (DM)-specific skin manifestations (heliotrope rash and Gottron’s sign) were frequently observed in patients with anti-Jo-1, anti-EJ, anti-PL-7, and anti-PL-12. Therefore, most clinical diagnoses were polymyositis or DM for anti-Jo-1, anti-EJ, and anti-PL-7; clinically amyopathic DM or ILD for anti-PL-12; and ILD for anti-KS and anti-OJ. Patients with anti-Jo-1, anti-EJ, and anti-PL-7 developed myositis later if they had ILD alone at the time of disease onset, and most patients with anti-ARS Abs eventually developed ILD if they did not have ILD at disease onset.Conclusion
Patients with anti-ARS Abs are relatively homogeneous. However, the distribution and timing of myositis, ILD, and rashes differ among patients with individual anti-ARS Abs. Thus, identification of individual anti-ARS Abs is beneficial to define this rather homogeneous subset and to predict clinical outcomes within the “anti-synthetase syndrome.” 相似文献78.
Hiroko Tabunoki Hiromasa Ono Hiroaki Ode Kazuhiro Ishikawa Natsuki Kawana Yutaka Banno Toru Shimada Yuki Nakamura Kimiko Yamamoto Jun-ichi Satoh Hidemasa Bono 《PloS one》2013,8(7)
Plasma uric acid (UA) levels decrease following clinical progression and stage development of Parkinson’s disease (PD). However, the molecular mechanisms underlying decreases in plasma UA levels remain unclear, and the potential to apply mutagenesis to a PD model has not previously been discovered. We identified a unique mutant of the silkworm Bombyx mori (B.mori) op. Initially, we investigated the causality of the phenotypic “op” by microarray analysis using our constructed KAIKO functional annotation pipeline. Consequently, we found a novel UA synthesis-modulating pathway, from DJ-1 to xanthine oxidase, and established methods for large-scale analysis of gene expression in B. mori. We found that the mRNA levels of genes in this pathway were significantly lower in B. mori op mutants, indicating that downstream events in the signal transduction cascade might be prevented. Additionally, levels of B.mori tyrosine hydroxylase (TH) and DJ-1 mRNA were significantly lower in the brain of B. mori op mutants. UA content was significantly lower in the B. mori op mutant tissues and hemolymph. The possibility that the B. mori op mutant might be due to loss of DJ-1 function was supported by the observed vulnerability to oxidative stress. These results suggest that UA synthesis, transport, elimination and accumulation are decreased by environmental oxidative stress in the B. mori op mutant. In the case of B. mori op mutants, the relatively low availability of UA appears to be due both to the oxidation of DJ-1 and to its expenditure to mitigate the effects of environmental oxidative stress. Our findings are expected to provide information needed to elucidate the molecular mechanism of decreased plasma UA levels in the clinical stage progression of PD. 相似文献
79.
Background
The precise mechanisms of the neuroprotective effects of insulin in streptozotocin (STZ)-induced diabetic animals remain unknown, but altered peripheral nerve insulin receptor signaling due to insulin deficiency might be one cause.Methodology and Principal Findings
Diabetes was induced in 10-week-old, male Wistar rats by injecting them with STZ (45 mg/kg). They were assigned to one group that received half of an insulin implant (∼1 U/day; I-group, n = 11) or another that remained untreated (U-group, n = 10) for 6 weeks. The controls were age- and sex-matched, non-diabetic Wistar rats (C-group, n = 12). Low-dose insulin did not change haemoglobin A1c, which increased by 136% in the U-group compared with the C-group. Thermal hypoalgesia and mechanical hyperalgesia developed in the U-group, but not in the I-group. Sensory and motor nerve conduction velocities decreased in the U-group, whereas sensory nerve conduction velocity increased by 7% (p = 0.0351) in the I-group compared with the U-group. Western blots showed unaltered total insulin receptor (IR), but a 31% decrease and 3.1- and 4.0-fold increases in phosphorylated IR, p44, and p42 MAPK protein levels, respectively, in sciatic nerves from the U-group compared with the C-group. Phosphorylated p44/42 MAPK protein decreased to control levels in the I-group (p<0.0001).Conclusions and Significance
Low-dose insulin deactivated p44/42 MAPK and ameliorated peripheral sensory nerve dysfunction in rats with STZ-induced diabetes. These findings support the notion that insulin deficiency per se introduces impaired insulin receptor signaling in type 1 diabetic neuropathy. 相似文献80.
Kazuhiro Hasegawa Daisaku OzawaTadakazu Ookoshi Hironobu Naiki 《Biochimica et Biophysica Acta - Proteins and Proteomics》2013,1834(8):1624-1631
Cerebral amyloid angiopathy is caused by deposition of the amyloid β-peptide which consists of mainly 39–40 residues to the cortical and leptomeningeal vessel walls. There are no definite in vitro systems to support the hypothesis that the vascular basement membrane may act as a scaffold of amyloid β-peptide carried by perivascular drainage flow and accelerate its amyloid fibril formation in vivo. We previously reported the critical roles of interfaces and agitation on the nucleation of amyloid fibrils at low concentrations of amyloid β-peptide monomers. Here, we reproduced the perivascular drainage flow in vitro by using N-hydroxysuccinimide-Sepharose 4 Fast flow beads as an inert stirrer in air-free wells rotated at 1 rpm. We then reproduced the basement membranes in the media of cerebral arteries in vitro by conjugating Matrigel and other proteins on the surface of Sepharose beads. These beads were incubated with 5 μM amyloid β(1–40) at 37 °C without air, where amyloid β(1–40) alone does not form amyloid fibrils. Using the initiation time of fibril growth kinetics (i.e., the lag time of fibril growth during which nuclei, on-pathway oligomers and protofibrils are successively formed) as a parameter of the efficiency of biological molecules to induce amyloid fibril formation, we found that basement membrane components including Matrigel, laminin, fibronectin, collagen type IV and fibrinogen accelerate the initiation of amyloid β-peptide fibril growth in vitro. These data support the essential role of vascular basement membranes in the development of cerebral amyloid angiopathy. 相似文献