全文获取类型
收费全文 | 1871篇 |
免费 | 127篇 |
出版年
2022年 | 14篇 |
2021年 | 22篇 |
2019年 | 16篇 |
2018年 | 41篇 |
2017年 | 24篇 |
2016年 | 40篇 |
2015年 | 53篇 |
2014年 | 53篇 |
2013年 | 88篇 |
2012年 | 107篇 |
2011年 | 99篇 |
2010年 | 61篇 |
2009年 | 60篇 |
2008年 | 93篇 |
2007年 | 83篇 |
2006年 | 96篇 |
2005年 | 92篇 |
2004年 | 94篇 |
2003年 | 77篇 |
2002年 | 76篇 |
2001年 | 41篇 |
2000年 | 65篇 |
1999年 | 44篇 |
1998年 | 21篇 |
1997年 | 28篇 |
1996年 | 21篇 |
1995年 | 22篇 |
1994年 | 17篇 |
1993年 | 15篇 |
1992年 | 40篇 |
1991年 | 33篇 |
1990年 | 31篇 |
1989年 | 25篇 |
1988年 | 27篇 |
1987年 | 24篇 |
1986年 | 17篇 |
1985年 | 11篇 |
1984年 | 13篇 |
1983年 | 26篇 |
1982年 | 11篇 |
1981年 | 12篇 |
1979年 | 10篇 |
1978年 | 13篇 |
1977年 | 13篇 |
1976年 | 9篇 |
1975年 | 10篇 |
1973年 | 16篇 |
1970年 | 10篇 |
1969年 | 18篇 |
1968年 | 12篇 |
排序方式: 共有1998条查询结果,搜索用时 31 毫秒
941.
942.
Sexually antagonistic selection generates intralocus sexual conflict, an evolutionary tug-of-war between males and females over optimal trait values [1-4]. Although the potential for this conflict is universal, the evolutionary importance of intralocus conflict is controversial because conflicts are typically thought to be resolvable through the evolution of sex-specific trait development [1-8]. However, whether sex-specific trait expression always resolves intralocus conflict has not been established. We assessed this with beetle populations subjected to bidirectional selection on an exaggerated sexually selected trait, the mandible. Mandibles are only ever developed in males for use in male-male combat, and larger mandibles increase male fitness (fighting [9, 10] and mating success, as we show here). We find that females from populations selected for larger male mandibles have lower fitness, whereas females in small-mandible populations have highest fitness, even though females never develop exaggerated mandibles. This is because mandible development changes genetically correlated characters, resulting in a negative intersexual fitness correlation across these populations, which is the unmistakable signature of intralocus sexual conflict [1]. Our results show that sex-limited trait development need not resolve intralocus sexual conflict, because traits are rarely, if ever, genetically independent of other characters [11]. Hence, intralocus conflict resolution is not as easy as currently thought. 相似文献
943.
Meiji Arai Kaori Kunisada Hye-Sook Kim Hirofumi Miyake Chiyoko Mizukoshi Toshifumi Kakutani 《Nucleosides, nucleotides & nucleic acids》2013,32(1-3):719-731
Abstract We have developed a colorimetric assay, “microtiter plate-hybridization”, for the detection of malaria parasites Plasmodium falciparum and P. vivax in human blood, in which the target DNA sequences (18s small subunit ribosomal RNA gene) amplified by polymerase chain reaction (PCR) are hybridized with the species-specific probes immobilized on a microtiter well. This assay system was tested in Guadalcanal, Solomon Islands, where malaria is highly endemic. We obtained blood samples by finger puncture from 130 asymptomatic donors. Among the 130 samples, 30 (23 %) were P. falciparum positive, 28 (22 %) were P. vivax positive, and 8 (6 %) were mixed infections. The results of our DNA diagnostic method showed good correlation with those of acridine orange microscopy. 相似文献
944.
Kensuke Ikenaka Kaori Kawai Masahisa Katsuno Zhe Huang Yue-Mei Jiang Yohei Iguchi Kyogo Kobayashi Tsubasa Kimata Masahiro Waza Fumiaki Tanaka Ikue Mori Gen Sobue 《PloS one》2013,8(2)
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons. We previously showed that the expression of dynactin 1, an axon motor protein regulating retrograde transport, is markedly reduced in spinal motor neurons of sporadic ALS patients, although the mechanisms by which decreased dynactin 1 levels cause neurodegeneration have yet to be elucidated. The accumulation of autophagosomes in degenerated motor neurons is another key pathological feature of sporadic ALS. Since autophagosomes are cargo of dynein/dynactin complexes and play a crucial role in the turnover of several organelles and proteins, we hypothesized that the quantitative loss of dynactin 1 disrupts the transport of autophagosomes and induces the degeneration of motor neuron. In the present study, we generated a Caenorhabditis elegans model in which the expression of DNC-1, the homolog of dynactin 1, is specifically knocked down in motor neurons. This model exhibited severe motor defects together with axonal and neuronal degeneration. We also observed impaired movement and increased number of autophagosomes in the degenerated neurons. Furthermore, the combination of rapamycin, an activator of autophagy, and trichostatin which facilitates axonal transport dramatically ameliorated the motor phenotype and axonal degeneration of this model. Thus, our results suggest that decreased expression of dynactin 1 induces motor neuron degeneration and that the transport of autophagosomes is a novel and substantial therapeutic target for motor neuron degeneration. 相似文献
945.
Chiori Yabuki Hidetoshi Komatsu Yoshiyuki Tsujihata Risa Maeda Ryo Ito Kae Matsuda-Nagasumi Kensuke Sakuma Kazumasa Miyawaki Naoya Kikuchi Koji Takeuchi Yugo Habata Masaaki Mori 《PloS one》2013,8(10)
Selective free fatty acid receptor 1 (FFAR1)/GPR40 agonist fasiglifam (TAK-875), an antidiabetic drug under phase 3 development, potentiates insulin secretion in a glucose-dependent manner by activating FFAR1 expressed in pancreatic β cells. Although fasiglifam significantly improved glycemic control in type 2 diabetes patients with a minimum risk of hypoglycemia in a phase 2 study, the precise mechanisms of its potent pharmacological effects are not fully understood. Here we demonstrate that fasiglifam acts as an ago-allosteric modulator with a partial agonistic activity for FFAR1. In both Ca2+ influx and insulin secretion assays using cell lines and mouse islets, fasiglifam showed positive cooperativity with the FFAR1 ligand γ-linolenic acid (γ-LA). Augmentation of glucose-induced insulin secretion by fasiglifam, γ-LA, or their combination was completely abolished in pancreatic islets of FFAR1-knockout mice. In diabetic rats, the insulinotropic effect of fasiglifam was suppressed by pharmacological reduction of plasma free fatty acid (FFA) levels using a lipolysis inhibitor, suggesting that fasiglifam potentiates insulin release in conjunction with plasma FFAs in vivo. Point mutations of FFAR1 differentially affected Ca2+ influx activities of fasiglifam and γ-LA, further indicating that these agonists may bind to distinct binding sites. Our results strongly suggest that fasiglifam is an ago-allosteric modulator of FFAR1 that exerts its effects by acting cooperatively with endogenous plasma FFAs in human patients as well as diabetic animals. These findings contribute to our understanding of fasiglifam as an attractive antidiabetic drug with a novel mechanism of action. 相似文献
946.
Koji Miyahara Kazuhiro Nouso Shunsuke Saito Sakiko Hiraoka Keita Harada Sakuma Takahashi Yuki Morimoto Sayo Kobayashi Fusao Ikeda Yasuhiro Miyake Hidenori Shiraha Akinobu Takaki Hiroyuki Okada Maho Amano Kazuko Hirose Shin-Ichiro Nishimura Kazuhide Yamamoto 《PloS one》2013,8(10)
Background
The aims of this study were to determine the change of whole-serum N-glycan profile in ulcerative colitis (UC) patients and to investigate its clinical utility.Methods
We collected serum from 75 UC patients at the time of admission and the same number of age/sex-matched healthy volunteers. Serum glycan profile was measured by comprehensive quantitative high-throughput glycome analysis and was compared with disease activity and prognosis.Results
Out of 61 glycans detected, 24 were differentially expressed in UC patients. Pathway analysis demonstrated that highly sialylated multi-branched glycans and agalactosyl bi-antennary glycans were elevated in UC patients; in addition, the glycan ratio m/z 2378/1914, which also increased in UC, showed the highest Area under Receiver Operating Characteristic curve (0.923) for the diagnosis of UC. Highly sialylated multi-branched glycans and the glycan ratio m/z 2378/1914 were higher in the patients with total colitis, Clinical Activity Index >10, Mayo endoscopic score 3, or a steroid-refractory status. In particular, the glycan ratio m/z 2378/1914 (above median) was an independent prognostic factor for the need for an operation (hazard ratio, 2.67; 95% confidence interval, 1.04–7.84).Conclusions
Whole-serum glycan profiles revealed that the glycan ratio m/z 2378/1914 and highly sialylated multi-branched glycans increase in UC patients, and are correlated with disease activity. The glycan ratio m/z 2378/1914 was an independent predictive factor of the prognosis of UC. 相似文献947.
Motoi Hashiba Masafumi Ono Hideyuki Hyogo Yukio Ikeda Kosei Masuda Reiko Yoshioka Yoichi Ishikawa Yuri Nagata Kensuke Munekage Tsunehiro Ochi Akira Hirose Yasuko Nozaki-Fujimura Shuhei Noguchi Nobuto Okamoto Kazuaki Chayama Narufumi Suganuma Toshiji Saibara 《PloS one》2013,8(11)
Patients with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) often have metabolic disorders including insulin resistance and type 2 diabetes mellitus (T2DM). We clarified the predictive factors in glucose metabolism for progression of hepatic fibrosis in patients with NAFLD by the 75-g oral glucose tolerance test (75gOGTT) and a continuous glucose monitoring system (CGMS). One hundred sixty-nine patients (68 female and 101 male patients) with biopsy-proven NAFLD with performance with 75gOGTT were enrolled and divided into four groups according to the stage of hepatic fibrosis (F0–3). The proportion of patients with T2DM significantly gradually increased, HbA1c and the homeostasis model assessment of insulin resistance were significantly elevated, and 1,5-anhydroglucitol (1,5-AG) was remarkably decreased with the progression of fibrosis. In the 75gOGTT, both plasma glucose and insulin secretion were remarkably increased with the progression of fibrosis. The only factor significantly associated with advanced fibrosis was 1,5-AG (P = 0.008) as determined by multivariate logistic regression analysis. We next evaluated the changes in blood glucose during 24 hours by monitoring with the CGMS to confirm the relationship between glycemic variability and progression of fibrosis. Variability of median glucose, standard deviation of median glucose (P = 0.0022), maximum blood glucose (P = 0.0019), and ΔMin–max blood glucose (P = 0.0029) were remarkably higher in severe fibrosis than in mild fibrosis.
Conclusion
Hyperinsulinemia and hyperglycemia, especially glycemic variability, are important predictive factors in glucose impairment for the progression of hepatic fibrosis in NAFLD. 相似文献948.
Eri Hara Akira Makino Kensuke Kurihara Manabu Sugai Akira Shimizu Isao Hara Eiichi Ozeki Shunsaku Kimura 《Biochimica et Biophysica Acta (BBA)/General Subjects》2013
Background
Nanoparticle of Lactosome, which is composed of poly(l-lactic acid)-base depsipeptide with diameter of 35 nm, accumulates in solid tumors by the enhanced permeability and retention (EPR) effect. However, a pharmacokinetic alteration of Lactosome was observed when Lactosome was repeatedly administered. This phenomenon is named as the Lactosome accelerated blood clearance (ABC) phenomenon. In this study, the effect of Lactosome dose on the ABC phenomenon was examined and discussed in terms of immune tolerance.Methods
To tumor transplanted mice, Lactosome (0–350 mg/kg) was administrated. At 7 days after the first administration, indocyanine green (ICG)-labeled Lactosome (ICG-Lactosome, 0–350 mg/kg) was injected. Near-infrared fluorescence imaging was performed, and biodistribution of ICG-Lactosome was evaluated. Further, the produced amounts of anti-Lactosome IgM were determined by enzyme-linked immunosorbent assay (ELISA).Results
ICG-Lactosome accumulated in the tumor region when the first Lactosome dose exceeded over 150 mg/kg. The amounts of anti-Lactosome IgM were inversely correlated with the first Lactosome doses. Even after establishment of the Lactosome ABC phenomenon with the first Lactosome dose as low as 5.0 mg/kg, the Lactosome ABC phenomenon can be evaded apparently by dosing ICG-Lactosome over 50 mg/kg regardless of anti-Lactosome IgM production.Conclusions
There are two different mechanisms for evasion from the Lactosome ABC phenomenon before and after its establishment. In either mechanism, however, the Lactosome ABC phenomenon can be evaded by excessive administration of Lactosome.General significance
Lactosome is a potential nanocarrier for drug and/or imaging agent delivery, which can be used for frequent administrations without significant pharmacokinetic alterations. 相似文献949.
Yusuke Fujii Thuy Tien Thi Nguyen Yuta Fujimura Naotaka Kameya Shoji Nakamura Kensuke Arakawa 《Bioscience, biotechnology, and biochemistry》2013,77(11):2144-2152
ABSTRACTStudies of Alzheimer’s disease are based on model mice that have been altered by transgenesis and other techniques to elicit pathogenesis. However, changes in the gut microbiota were recently suggested to diminish cognitive function in patients, as well as in model mice. Accordingly, we have created model mice of the human gut microbiota by transplanting germ-free C57BL/6N mice with fecal samples from a healthy volunteer and from an affected patient. These humanized mice were stably colonized and reproduced the bacterial diversity in donors. Remarkably, performance on Object Location Test and Object Recognition Test was significantly reduced in the latter than in the former at 55 weeks of age, suggesting that gut microbiota transplanted from an affected patient affects mouse behavior. In addition, metabolites related to the nervous system, including γ-aminobutyrate, taurine, and valine, were significantly less abundant in the feces of mice transplanted with microbiota from the affected patient. 相似文献
950.
Kensuke Nabeta Teruyo Kasai Hiroshi Sugisawa 《Bioscience, biotechnology, and biochemistry》2013,77(10):2103-2104
We investigated the effect of 17β-estradiol (E2) on the expression of daintain/AIF-1, a marker of activated macrophages, in RAW264.7. E2 upregulated the protein and mRNA levels of daintain/AIF-1 in similar manners under physiological concentrations of 10?11 M to 10?7 M. The application of ICI 182,780, an estrogen receptor (ER) antagonist, attenuated E2-induced daintain/AIF-1 production, suggesting the involvement of ER in this process. 相似文献