全文获取类型
收费全文 | 1521篇 |
免费 | 102篇 |
出版年
2021年 | 21篇 |
2020年 | 9篇 |
2019年 | 8篇 |
2018年 | 28篇 |
2017年 | 20篇 |
2016年 | 36篇 |
2015年 | 52篇 |
2014年 | 61篇 |
2013年 | 85篇 |
2012年 | 125篇 |
2011年 | 97篇 |
2010年 | 49篇 |
2009年 | 53篇 |
2008年 | 94篇 |
2007年 | 99篇 |
2006年 | 91篇 |
2005年 | 84篇 |
2004年 | 86篇 |
2003年 | 83篇 |
2002年 | 76篇 |
2001年 | 17篇 |
2000年 | 23篇 |
1999年 | 22篇 |
1998年 | 8篇 |
1997年 | 7篇 |
1995年 | 6篇 |
1994年 | 9篇 |
1993年 | 16篇 |
1992年 | 14篇 |
1991年 | 7篇 |
1990年 | 11篇 |
1989年 | 14篇 |
1988年 | 8篇 |
1987年 | 13篇 |
1986年 | 13篇 |
1985年 | 22篇 |
1984年 | 8篇 |
1983年 | 11篇 |
1981年 | 10篇 |
1980年 | 8篇 |
1979年 | 7篇 |
1977年 | 9篇 |
1976年 | 10篇 |
1975年 | 7篇 |
1974年 | 11篇 |
1973年 | 10篇 |
1970年 | 9篇 |
1969年 | 6篇 |
1968年 | 7篇 |
1966年 | 7篇 |
排序方式: 共有1623条查询结果,搜索用时 15 毫秒
991.
Fujita N Nakanishi M Mukai J Naito Y Ichida T Kaito M Yoshikawa T Takei Y 《Molecular medicine (Cambridge, Mass.)》2011,17(1-2):70-78
Recent development of proteomic array technology, including protein profiling coupling ProteinChip array with surface-enhanced laser desorption ionization time-of-flight mass spectrometry (SELDI-TOF/MS), provides a potentially powerful tool for discovery of new biomarkers by comparison of its profiles according to patient phenotypes. We used this approach to identify the host factors associated with treatment response in patients with chronic hepatitis C (CHC) receiving a 48-wk course of pegylated interferon (PEG-IFN) alpha 2b plus ribavirin (RBV). Protein profiles of pretreatment serum samples from 32 patients with genotype 1b and high viral load were conducted by SELDI-TOF/MS by using the three different ProteinChip arrays (CM10, Q10, IMAC30). Proteins showed significantly different peak intensities between sustained virological responders (SVRs), and non-SVRs were identified by chromatography, SDS-PAGE, TOF/MS and tandem mass spectrometry (MS/MS) assay. Eleven peak intensities were significantly different between SVRs and non-SVRs. The three SVR-increased peaks could be identified as two apolipoprotein (Apo) fragments and albumin and, among the eight non-SVR-increased proteins, four peaks identified as two iron-related and two fibrogenesis-related protein fragments, respectively. Multivariate analysis showed that the serum ferritin and three peak intensity values (Apo A1, hemopexin and transferrin) were independent variables associated with SVRs, and the area under the receiver operating characteristic (ROC) curves for SVR prediction by using the Apo A1/hemopexin and hemopexin/transferrin were 0.964 and 0.936. In conclusion, pretreatment serum protein profiling by SELDI-TOF/MS is variable for identification of response-related host factors, which are useful for treatment efficacy prediction in CHC receiving PEG-IFN plus RBV. Our data also may help us understand the mechanism for treatment resistance and development of more effective antiviral therapy targeted toward the modulation of lipogenesis or iron homeostasis in CHC patients. 相似文献
992.
993.
PurposeThis study was to assess the clinical relevance of the blood granulocytes to lymphocytes (G/L) ratio as an early marker of surgical stress in patients with colorectal cancer.MethodsThirty-three patients with colorectal cancer were prospectively to undergo laparoscopic-assisted (n = 12) or open (n = 21) surgical resection. Granulocyte and lymphocyte counts were used to calculate the G/L ratios in blood samples from all patients before the operation and post-operatively on days 1, 3 and 7. Additionally, serum inflammatory cytokines, interleukin (IL)-1β, IL-6, IL-8, tumour necrosis factor (TNF)-α, granulocyte colony-stimulating factor (G-CSF) and macrophage (M)-CSF were assayed as markers of surgical stress.ResultsSeven of 33 patients developed unexpected complications. Serum IL-6 (P < 0.0001), G-CSF (P = 0.0257), and M-CSF (P < 0.0001) were higher on day 1 vs before the operation. Similarly, the G/L ratios were higher on days 1–3 vs before the operation (P < 0.0001) and then gradually decreased together with the surgical stress levels. The G/L ratios and the numbers of granulocytes and lymphocytes in the blood showed no correlation with serum IL-1β or TNF-α. In contrast, the G/L ratios and the numbers of granulocytes in the blood showed significant correlation with IL-6 (Rs = 0.710, P < 0.0001, Rs = 0.653, P < 0.0001, respectively), with G-CSF (Rs = 0.626, P < 0.0001, Rs = 0.578, P < 0.0001), with M-CSF (Rs = 0.470, P < 0.0001, Rs = 0.372, P < 0.0001). However, the number of lymphocytes showed inverse correlation with IL-6 (Rs = ?0.493, P < 0.0001), G-CSF (Rs = ?0.440, P < 0.0001) and M-SCF (Rs = ?0.443, P < 0.0001).ConclusionThe G/L ratio appears to be a simple and clinically relevant parameter for the assessment of perioperative stress in patients undergoing colorectal surgery. 相似文献
994.
Akao T Yashiro I Hosoyama A Kitagaki H Horikawa H Watanabe D Akada R Ando Y Harashima S Inoue T Inoue Y Kajiwara S Kitamoto K Kitamoto N Kobayashi O Kuhara S Masubuchi T Mizoguchi H Nakao Y Nakazato A Namise M Oba T Ogata T Ohta A Sato M Shibasaki S Takatsume Y Tanimoto S Tsuboi H Nishimura A Yoda K Ishikawa T Iwashita K Fujita N Shimoi H 《DNA research》2011,18(6):423-434
The term 'sake yeast' is generally used to indicate the Saccharomyces cerevisiae strains that possess characteristics distinct from others including the laboratory strain S288C and are well suited for sake brewery. Here, we report the draft whole-genome shotgun sequence of a commonly used diploid sake yeast strain, Kyokai no. 7 (K7). The assembled sequence of K7 was nearly identical to that of the S288C, except for several subtelomeric polymorphisms and two large inversions in K7. A survey of heterozygous bases between the homologous chromosomes revealed the presence of mosaic-like uneven distribution of heterozygosity in K7. The distribution patterns appeared to have resulted from repeated losses of heterozygosity in the ancestral lineage of K7. Analysis of genes revealed the presence of both K7-acquired and K7-lost genes, in addition to numerous others with segmentations and terminal discrepancies in comparison with those of S288C. The distribution of Ty element also largely differed in the two strains. Interestingly, two regions in chromosomes I and VII of S288C have apparently been replaced by Ty elements in K7. Sequence comparisons suggest that these gene conversions were caused by cDNA-mediated recombination of Ty elements. The present study advances our understanding of the functional and evolutionary genomics of the sake yeast. 相似文献
995.
996.
Xiaotong Zhu Kazuhide Yahata Jean Semé Fils Alexandre Takafumi Tsuboi Osamu Kaneko 《Parasitology international》2013,62(2):215-229
Plasmodium falciparum SURFIN is a type I transmembrane protein that shares domains with molecules expressed on the surface of the red blood cells (RBCs) infected with a variety of malaria parasite species, such as P. falciparum PfEMP1, Plasmodium vivax VIR proteins, and Plasmodium knowlesi SICAvar. Thus, understanding the export mechanism of SURFIN to the RBC may provide fundamental insights into how malaria parasites export their proteins to RBC cytosol in general. We re-evaluate SURFIN4.1 for its exon–intron boundaries, location, and the function of each region by expressing recombinant SURFIN4.1 in P. falciparum. We found that, in two 3D7 lines and one Thai isolate, SURFIN4.1 possesses only 19 amino acids after the predicted transmembrane region, whereas in the FCR3 line, it possesses two tryptophan-rich domains in its intracellular region. Recombinant SURFIN4.1 based on the 3D7 sequence was detected in the Maurer's clefts of infected RBCs, suggesting that endogenous SURFIN4.1 is also exported to Maurer's clefts. Brefeldin A-sensitive export of SURFIN4.1 indicates that its export is endoplasmic reticulum (ER)/Golgi-dependent. By sequential deletion and replacement with unrelated protein sequences, we find that the SURFIN4.1 transmembrane region is essential for the initial recruitment of the protein to the ER, and the following sorting step to the parasitophorous vacuole is determined by two independent signals located in the N-terminus 50 amino acids. TM region with the adjacent cytoplasmic region also contains information for the efficient recruitment to the ER and/or for the efficient translocation across the parasitophorous vacuole membrane. We also found that SURFIN4.1 might form a homomeric complex during the trafficking using cysteine rich domain and/or variable region. 相似文献
997.
Kazuhiro Nakaya Makoto Ayaori Harumi Uto-Kondo Grace Megumi Sotherden Takafumi Nishida Haruka Katamoto Yuko Miura Shunichi Takiguchi Emi Yakushiji Maki Iizuka Masatsune Ogura Makoto Sasaki Makiko Yogo Tomohiro Komatsu Takeshi Adachi Chizuko Maruyama Katsunori Ikewaki 《Biochimica et Biophysica Acta (BBA)/Molecular and Cell Biology of Lipids》2013,1831(8):1402-1411
Stearoyl-coenzyme A desaturase 1 (SCD1) is the rate-limiting enzyme in the synthesis of monounsaturated fatty acids. However, the impact of SCD1 on atherosclerosis remains unclear. The aim of this study was to determine whether SCD1 affects macrophage reverse cholesterol transport (RCT) in mice. Compared to the control, adenoviral-mediated SCD1 overexpression in RAW264.7 macrophages increased cholesterol efflux to HDL, but not to apoA-I, without clear changes in ABCA1, ABCG1 and SR-BI expressions. While knockdown of ABCG1 and SR-BI did not affect the SCD1-induced cholesterol efflux to HDL, SCD1-overexpressing macrophages promoted the formation of both normal- and large-sized HDL in media, accompanying increased apolipoprotein A-I levels in HDL fractions. Transformation to larger particles of HDL was independently confirmed by nuclear magnetic resonance-based lipoprotein analysis. Interestingly, media transfer assays revealed that HDL generated by SCD1 had enhanced cholesterol efflux potential, indicating that SCD1 transformed HDL to a more anti-atherogenic phenotype. To study macrophage RCT in vivo, 3H-cholesterol-labeled RAW264.7 cells overexpressing SCD1 or the control were intraperitoneally injected into mice. Supporting the in vitro data, injection of SCD1-macrophages resulted in significant increases in 3H-tracer in plasma, liver, and feces compared to the control. Moreover, there was a shift towards larger particles in the 3H-tracer distribution of HDL fractions obtained from the mice. 相似文献
998.
Yoshitaka Kondo Goji Hasegawa Hiroshi Okada Takafumi Senmaru Michiaki Fukui Naoto Nakamura Morio Sawada Jo Kitawaki Takeshi Okanoue Yuki Kishimoto Akiko Amano Naoki Maruyama Hiroshi Obayashi Akihito Ishigami 《PloS one》2013,8(6)
Background/Aims
The senescence marker protein-30 (SMP30) is a 34 kDa protein originally identified in rat liver that shows decreased levels with age. Several functional studies using SMP30 knockout (Smp30Y/−) mice established that SMP30 functions as an antioxidant and protects against apoptosis. To address the potential role of SMP30 in nonalcoholic fatty liver disease (NAFLD) pathogenesis, we established Smp30Y/− mice on a Leprdb/db background (Leprdb/dbSmp30Y/− mice).Research Design/Principal Findings
Male Leprdb/dbSmp30Y/− mice were fed a standard diet (340 kcal/100 g, fat 5.6%) for 16 weeks whereupon the lipid/lipoprotein profiles, hepatic expression of genes related to lipid metabolism and endoplasmic reticulum stress markers were analyzed by HPLC, quantitative RT-PCR and western blotting, respectively. Changes in the liver at a histological level were also investigated. The amount of SMP30 mRNA and protein in livers was decreased in Leprdb/dbSmp30Y/+ mice compared with Leprdb/+Smp30Y/+ mice. Compared with Leprdb/dbSmp30Y/+ mice, 24 week old Leprdb/dbSmp30Y/− mice showed: i) increased small dense LDL-cho and decreased HDL-cho levels; ii) fatty liver accompanied by numerous inflammatory cells and increased oxidative stress; iii) decreased mRNA expression of genes involved in fatty acid oxidation (PPARα) and lipoprotein uptake (LDLR and VLDLR) but increased CD36 levels; and iv) increased endoplasmic reticulum stress.Conclusion
Our data strongly suggest that SMP30 is closely associated with NAFLD pathogenesis, and might be a possible therapeutic target for NAFLD. 相似文献999.
Kazushi Yamane Fumiharu Kimura Kiichi Unoda Takafumi Hosokawa Takahiko Hirose Hiroki Tani Yoshimitsu Doi Simon Ishida Hideto Nakajima Toshiaki Hanafusa 《PloS one》2013,8(7)
Background
Pulmonary thromboembolism is a common cause of death in patients with autopsy-confirmed Parkinsonism. This study investigated the incidence of leg deep vein thrombosis in Parkinson’s disease and relationships between deep vein thrombosis and clinical/laboratory findings, including postural abnormalities as assessed by photographic measurements.Methods
This cross-sectional study assessed the presence of deep vein thrombosis using bilateral leg Doppler ultrasonography in 114 asymptomatic outpatients with Parkinson’s disease.Results
Deep vein thrombosis was detected in 23 patients (20%) with Parkinson’s disease. Deep vein thrombosis was located in the distal portion in 18 patients and in the proximal portion in 5 patients. No significant differences in age, sex, body mass index, disease duration, Hoehn-Yahr stage, anti-Parkinson’s drugs, or daily levodopa-equivalent dose were seen between deep vein thrombosis-positive and -negative groups. Univariate analysis for developing deep vein thrombosis in patients with Parkinson’s disease identified the following markers: long-term wheelchair use, bent knee, bent spine, and D-dimer elevation. Bending angles were significantly greater in the deep vein thrombosis-positive group at the knee and spine than in the deep vein thrombosis-negative group. Half of Parkinson’s disease patients with camptocormia had deep vein thrombosis. Among diabetes mellitus cases, long-term wheelchair use, bent knee over 15°, camptocormia, D-dimer elevation, the more risk markers were associated with a higher incidence of DVT. The presence of risk markers contributed to the development of deep vein thrombosis. On multivariate logistic regression analysis, a bent knee posture was strongly associated with an increased risk of deep vein thrombosis.Conclusion
Presence of leg deep vein thrombosis correlated with postural abnormalities in Parkinson’s disease. We recommend non-invasive ultrasonographic screening for leg deep vein thrombosis in these high-risk patients with Parkinson’s disease. 相似文献1000.
M Yamamoto-Tanaka T Makino A Motoyama M Miyai R Tsuboi T Hibino 《Cell death & disease》2014,5(4):e1181
Loss of the nucleus is a critical step in keratinocyte terminal differentiation. To elucidate the mechanisms involved, we focused on two characteristic events: nuclear translocation of N-terminal fragment of profilaggrin and caspase-14-dependent degradation of the inhibitor of caspase-activated DNase (ICAD). First, we demonstrated that epidermal mesotrypsin liberated a 55-kDa N-terminal fragment of profilaggrin (FLG-N) and FLG-N was translocated into the nucleus. Interestingly, these cells became TUNEL positive. Mutation in the mesotrypsin-susceptible Arg-rich region between FLG-N and the first filaggrin domain abolished these changes. Furthermore, caspase-14 caused limited proteolysis of ICAD, followed by accumulation of caspase-activated DNase (CAD) in TUNEL-positive nuclei. Knockdown of both proteases resulted in a significant increase of remnant nuclei in a skin equivalent model. Immunohistochemical study revealed that both caspase-14 and mesotrypsin were markedly downregulated in parakeratotic areas of lesional skin from patients with atopic dermatitis and psoriasis. Collectively, our results indicate that at least two pathways are involved in the DNA degradation process during keratinocyte terminal differentiation. 相似文献