全文获取类型
收费全文 | 2869篇 |
免费 | 151篇 |
国内免费 | 1篇 |
出版年
2022年 | 11篇 |
2021年 | 24篇 |
2020年 | 17篇 |
2019年 | 17篇 |
2018年 | 25篇 |
2017年 | 22篇 |
2016年 | 45篇 |
2015年 | 63篇 |
2014年 | 82篇 |
2013年 | 233篇 |
2012年 | 138篇 |
2011年 | 134篇 |
2010年 | 83篇 |
2009年 | 85篇 |
2008年 | 130篇 |
2007年 | 147篇 |
2006年 | 120篇 |
2005年 | 145篇 |
2004年 | 146篇 |
2003年 | 154篇 |
2002年 | 135篇 |
2001年 | 65篇 |
2000年 | 88篇 |
1999年 | 82篇 |
1998年 | 40篇 |
1997年 | 34篇 |
1996年 | 30篇 |
1995年 | 21篇 |
1994年 | 18篇 |
1993年 | 28篇 |
1992年 | 55篇 |
1991年 | 55篇 |
1990年 | 55篇 |
1989年 | 60篇 |
1988年 | 46篇 |
1987年 | 53篇 |
1986年 | 27篇 |
1985年 | 36篇 |
1984年 | 16篇 |
1983年 | 16篇 |
1982年 | 25篇 |
1981年 | 18篇 |
1980年 | 13篇 |
1979年 | 27篇 |
1978年 | 19篇 |
1977年 | 19篇 |
1976年 | 18篇 |
1975年 | 16篇 |
1974年 | 14篇 |
1973年 | 16篇 |
排序方式: 共有3021条查询结果,搜索用时 31 毫秒
991.
Ohta K Sekiya M Uozaki H Igarashi M Takase S Kumagai M Takanashi M Takeuchi Y Izumida Y Kubota M Nishi M Okazaki H Iizuka Y Yahagi N Yagyu H Fukayama M Kadowaki T Ohashi K Ishibashi S Osuga J 《Biochemical and biophysical research communications》2011,(1):254-260
We have previously demonstrated that neutral cholesterol ester hydrolase 1 (Nceh1) regulates foam cell formation and atherogenesis through the catalytic activity of cholesterol ester hydrolysis, and that Nceh1 and hormone-sensitive lipase (Lipe) are responsible for the majority of neutral cholesterol ester hydrolase activity in macrophages. There are several cholesterol ester-metabolizing tissues and cells other than macrophages, among which adrenocortical cells are also known to utilize the intracellular cholesterol for steroidogenesis. It has been believed that the mobilization of intracellular cholesterol ester in adrenal glands was facilitated solely by Lipe. We herein demonstrate that Nceh1 is also involved in cholesterol ester hydrolysis in adrenal glands. While Lipe deficiency remarkably reduced the neutral cholesterol ester hydrolase activity in adrenal glands as previously reported, additional inactivation of Nceh1 gene completely abrogated the activity. Adrenal glands were enlarged in proportion to the degree of reduced neutral cholesterol ester hydrolase activity, and the enlargement of adrenal glands and the accumulation of cholesterol esters were most pronounced in the Nceh1/Lipe double-deficient mice. Thus Nceh1 is involved in the adrenal cholesterol metabolism, and the cholesterol ester hydrolytic activity in adrenal glands is associated with the organ enlargement. 相似文献
992.
Interaction and inhibitory effect of ammonium cation in the oxygen evolving center of photosystem II
Photosynthetic O(2) evolution takes place at the Mn cluster in photosystem II (PSII) by oxidation of water. It has been proposed that ammonia, one of water analogues, functions as an inhibitor of O(2) evolution at alkaline pH. However, the detailed mechanism of inhibition has not been understood yet. In this study, we investigated the mechanism of ammonia inhibition by examining the NH(4)Cl-induced inhibition of O(2) evolution in a wide pH range (pH 5.0-8.0) and by detecting the interaction site using Fourier transform infrared (FTIR) spectroscopy. In addition to intact PSII membranes from spinach, PSII membranes depleted of the PsbP and PsbQ extrinsic proteins were used as samples to avoid the effect of the release of these proteins by salt treatments. In both types of samples, oxygen evolution activity decreased by approximately 40% by addition of 100 mM NH(4)Cl in the range of pH 5.0-8.0. The presence of inhibition at acidic pH without significant pH dependence strongly suggests that NH(4)(+) cation functions as a major inhibitor in the acidic pH region, where neutral NH(3) scarcely exists in the buffer. The NH(4)Cl treatment at pH 6.5 and 5.5 induced prominent changes in the COO(-) stretching regions in FTIR difference spectra upon the S(1) → S(2) transition measured at 283 K. The NH(4)Cl concentration dependence of the amplitude of the spectral changes showed a good correlation with that of the inhibition of O(2) evolution. From this observation, it is proposed that NH(4)(+) cation interacts with carboxylate groups coupled to the Mn cluster as direct ligands or proton transfer mediators, causing inhibition of the O(2) evolving reaction. 相似文献
993.
Munkhbold Tuul Hiroyuki Kitao Makoto Iimori Kazuaki Matsuoka Shinichi Kiyonari Hiroshi Saeki Eiji Oki Masaru Morita Yoshihiko Maehara 《PloS one》2013,8(2)
Hyperthermia is widely used to treat patients with cancer, especially in combination with other treatments such as radiation therapy. Heat treatment per se activates DNA damage responses mediated by the ATR-Chk1 and ATM-Chk2 pathways but it is not fully understood how these DNA damage responses are activated and affect heat tolerance. By performing a genetic analysis of human HeLa cells and chicken B lymphoma DT40 cells, we found that heat-induced Chk1 Ser345 phosphorylation by ATR was largely dependent on Rad9, Rad17, TopBP1 and Claspin. Activation of the ATR-Chk1 pathway by heat, however, was not associated with FancD2 monoubiquitination or RPA32 phosphorylation, which are known as downstream events of ATR kinase activation when replication forks are stalled. Downregulation of ATR, Rad9, Rad17, TopBP1 or Claspin drastically reduced clonogenic cell viability upon hyperthermia, while gene knockout or inhibition of ATM kinase reduced clonogenic viability only modestly. Suppression of the ATR-Chk1 pathway activation enhanced heat-induced phosphorylation of Chk2 Thr68 and simultaneous inhibition of ATR and ATM kinases rendered severe heat cytotoxicity. These data indicate that essential factors for activation of the ATR-Chk1 pathway at stalled replication forks are also required for heat-induced activation of ATR kinase, which predominantly contributes to heat tolerance in a non-overlapping manner with ATM kinase. 相似文献
994.
995.
We recently reported that microRNA (miR)-145 is downregulated and induces apoptosis in human bladder cancer cells. Also, it is suggested that the ectopic expression of miR-145 induces apoptosis with the induction of TRAIL expression in several cancer cells. Here, we demonstrated a novel mechanism of apoptosis induction by miR-145 in bladder cancer cells. Exogenous miR-145 in T24 and NKB1 cells markedly increased the expression levels of interferon (IFN)-β, 2′–5′-oligoadenylate synthetase 1, which lies upstream of 2′–5′ oligoadenylates/RNase L system, and TRAIL, and induced apparent caspase-dependent apoptosis that was suppressed by cotreatment with a pan-caspase inhibitor; moreover, these expression levels were reduced by cotreatment with an miR-145 inhibitor. The apoptosis did not depend on Toll-like receptor 3 (TLR3) expression, because TLR3-silencing failed to inhibit IFN-β induction by miR-145. Then, we focused on the suppressor of cytokine signaling 7 (socs7), whose expression level was upregulated in bladder cancer cells compared with its level in normal human urothelial cells, as a putative target gene involved in IFN-β induction by miR-145. Expectedly, exogenous miR-145 decreased the expression level of SOCS7, and socs7-silencing enhanced IFN-β induction by transfection with a TLR3 ligand, polyinosinic acid-polycytidylic acid (PIC). The results of a luciferase reporter assay revealed that miR-145 targeted socs7. In addition, socs7-silencing significantly decreased the level of p-Akt and suppressed the growth of T24 cells. Furthermore, exogenous miR-145 or socs7-silencing promoted nuclear translocation of STAT3. In conclusion, the machinery of IFN-β induction through the regulation of SOCS7 by miR-145 was closely associated with the induction of apoptosis. Moreover, exogenous miR-145 promoted IFN-β induction by targeting socs7, which resulted in the nuclear translocation of STAT3. Additionally, our data indicate that SOCS7 functioned as an oncogene, the finding that revealed a novel mechanism of carcinogenesis in bladder cancer cells. 相似文献
996.
Jiro Harada Tadashi Mizoguchi Souichirou Satoh Yusuke Tsukatani Makio Yokono Masato Noguchi Ayumi Tanaka Hitoshi Tamiaki 《PloS one》2013,8(4)
The gene named bciD, which encodes the enzyme involved in C7-formylation in bacteriochlorophyll e biosynthesis, was found and investigated by insertional inactivation in the brown-colored green sulfur bacterium Chlorobaculum limnaeum (previously called Chlorobium phaeobacteroides). The bciD mutant cells were green in color, and accumulated bacteriochlorophyll c homologs bearing the 7-methyl group, compared to C7-formylated BChl e homologs in the wild type. BChl-c homolog compositions in the mutant were further different from those in Chlorobaculum tepidum which originally produced BChl c: (31
S)-8-isobutyl-12-ethyl-BChl c was unusually predominant. 相似文献
997.
Relationships among Smoking Habits,Airflow Limitations,and Metabolic Abnormalities in School Workers
Masafumi Horie Satoshi Noguchi Wakae Tanaka Yasushi Goto Hisanao Yoshihara Masaki Kawakami Masaru Suzuki Yoshio Sakamoto 《PloS one》2013,8(11)
Background
Chronic obstructive pulmonary disease is caused mainly by habitual smoking and is common among elderly individuals. It involves not only airflow limitation but also metabolic disorders, leading to increased cardiovascular morbidity and mortality.Objective
We evaluated relationships among smoking habits, airflow limitation, and metabolic abnormalities.Methods
Between 2001 and 2008, 15,324 school workers (9700 males, 5624 females; age: ≥30 years) underwent medical checkups, including blood tests and spirometry. They also responded to a questionnaire on smoking habits and medical history.Results
Airflow limitation was more prevalent in current smokers than in ex-smokers and never-smokers in men and women. The frequency of hypertriglyceridemia was higher in current smokers in all age groups, and those of low high-density-lipoprotein cholesterolemia and diabetes mellitus were higher in current smokers in age groups ≥ 40 s in men, but not in women. There were significant differences in the frequencies of metabolic abnormalities between subjects with airflow limitations and those without in women, but not in men. Smoking index was an independent factor associated with increased frequencies of hypertriglyceridemia (OR 1.015; 95% CI: 1.012–1.018; p<0.0001) and low high-density-lipoprotein cholesterolemia (1.013; 1.010–1.016; p<0.0001) in men. Length of smoking cessation was an independent factor associated with a decreased frequency of hypertriglyceridemia (0.984; 0.975–0.994; p = 0.007).Conclusions
Habitual smoking causes high incidences of airflow limitation and metabolic abnormalities. Women, but not men, with airflow limitation had higher frequencies of metabolic abnormalities. 相似文献998.
Yoshimasa Imoto Takahiro Tokunaga Yuri Matsumoto Yuko Hamada Mizuho Ono Takechiyo Yamada Yumi Ito Tadao Arinami Mitsuhiro Okano Emiko Noguchi Shigeharu Fujieda 《PloS one》2013,8(8)
Seasonal allergic rhinitis (SAR) to the Japanese cedar, Cryptomeria japonica (JC) pollen is an IgE-mediated type I allergy affecting nasal mucosa. However, the molecular events underlying its development remain unclear. We sought to identify SAR-associated altered gene expression in nasal epithelial cells during natural exposure to JC pollen. We recruited study participants in 2009 and 2010 and collected nasal epithelial cells between February and April, which is the period of natural pollen dispersion. Fifteen patients with SAR-JC and 13 control subjects were enrolled in 2009, and 17 SAR-JC patients, 13 sensitized asymptomatic subjects (Sensitized), and 15 control subjects were enrolled in 2010. Total RNA was extracted from nasal epithelial cells and 8 SAR-JC patients and 6 control subjects in 2009 were subjected to microarray analysis with the Illumina HumanRef-8 Expression BeadChip platform. Allergen-stimulated histamine release was examined in the peripheral blood basophils isolated from patients with SAR. We identified 32 genes with significantly altered expression during allergen exposure. One of these, CST1 encodes the cysteine protease inhibitor, cystatin SN. CST1 expression in nasal epithelial cells was significantly upregulated in both the 2009 and 2010 SAR-JC groups compared with the control groups. Immunohistochemical staining confirmed the increased expression of CST1 in the nasal epithelial cells of SAR patients. Addition of exogenous CST1 to basophils inhibited JC allergen-stimulated histamine release in vitro. We propose that CST1 may contribute to inactivation of protease allergens and help re-establish homeostasis of the nasal membranes. 相似文献
999.
Akiko Shiotani Takahisa Murao Yoshihiko Fujita Yoshinori Fujimura Takashi Sakakibara Kazuto Nishio Ken Haruma 《PloS one》2013,8(12)
Background
Aspirin-induced enteropathy is now increasingly being recognized although the pathogenesis of small intestinal damage induced by aspirin is not well understood and related risk factors have not been established.Aim
To investigate pharmacogenomic profile of low dose aspirin (LDA)-induced small bowel bleeding.Methods
Genome-wide analysis of single nucleotide polymorphisms (SNPs) was performed using the Affymetrix DMET™ Plus Premier Pack. Genotypes of candidate genes associated with small bowel bleeding were determined using TaqMan SNP Genotyping Assay kits and direct sequencing.Results
In the validation study in overall 37 patients with small bowel bleeding and 400 controls, 4 of 27 identified SNPs: CYP4F11 (rs1060463) GG (p=0.003), CYP2D6 (rs28360521) GG (p=0.02), CYP24A1 (rs4809957) T allele (p=0.04), and GSTP1 (rs1695) G allele (p=0.04) were significantly more frequent in the small bowel bleeding group compared to the controls. After adjustment for significant factors, CYP2D6 (rs28360521) GG (OR 4.11, 95% CI. 1.62 -10.4) was associated with small bowel bleeding.Conclusions
CYP4F11 and CYP2D6 SNPs may identify patients at increased risk for aspirin-induced small bowel bleeding. 相似文献1000.
Haruka Kaneko Muneaki Ishijima Ippei Futami Naoki Tomikawa-Ichikawa Keisuke Kosaki Ryo Sadatsuki Yoshihiko Yamada Hisashi Kurosawa Kazuo Kaneko Eri Arikawa-Hirasawa 《Matrix biology》2013,32(3-4):178-187
The osteophyte associated with osteoarthritis (OA) is a bony outgrowth formed at the margins of the affected joint through endochondral ossification-like processes. However, the mechanism of osteophyte formation and its pathogenesis are unclear. Perlecan (Hspg2), a heparan sulfate proteoglycan, is expressed in many extracellular tissues and plays critical roles in skeletal development and diseases. The aim of the present study is to identify the role of synovial perlecan in osteophyte formation using perinatal lethality rescued perlecan-knockout mice (Hspg2?/?-Tg) wherein perlecan expression is lacking in the synovial and other tissues, except for cartilage. We analyzed the development of osteophytes in joints of Hspg2?/?-Tg mice in two different animal models: the surgical OA model, in which the medial collateral ligament was transected and the medial meniscus was resected, and the TGF-β-induced osteophyte formation model. In the surgical OA model, the osteophyte size and maturation were significantly reduced in the OA joints of Hspg2?/?-Tg mice compared with control mice, while OA developed on the medial side of the knee joints with no differences in the cartilage degradation score or synovitis score between control and Hspg2?/?-Tg mice. The reduced osteophyte formation in Hspg2?/?-Tg mice was associated with reduced cell proliferation and chondrogenesis. In the TGF-β model, the osteophyte size and maturation were also significantly reduced in Hspg2?/?-Tg mice compared with control mice. Our findings suggest that synovial perlecan plays an important role in osteophyte development in OA, and they provide insights that may facilitate the development of OA therapy. 相似文献