全文获取类型
收费全文 | 6468篇 |
免费 | 506篇 |
国内免费 | 432篇 |
专业分类
7406篇 |
出版年
2024年 | 15篇 |
2023年 | 92篇 |
2022年 | 193篇 |
2021年 | 329篇 |
2020年 | 218篇 |
2019年 | 273篇 |
2018年 | 240篇 |
2017年 | 159篇 |
2016年 | 269篇 |
2015年 | 426篇 |
2014年 | 470篇 |
2013年 | 509篇 |
2012年 | 603篇 |
2011年 | 522篇 |
2010年 | 327篇 |
2009年 | 296篇 |
2008年 | 331篇 |
2007年 | 294篇 |
2006年 | 222篇 |
2005年 | 225篇 |
2004年 | 188篇 |
2003年 | 151篇 |
2002年 | 124篇 |
2001年 | 110篇 |
2000年 | 98篇 |
1999年 | 106篇 |
1998年 | 43篇 |
1997年 | 59篇 |
1996年 | 47篇 |
1995年 | 44篇 |
1994年 | 33篇 |
1993年 | 35篇 |
1992年 | 42篇 |
1991年 | 37篇 |
1990年 | 46篇 |
1989年 | 37篇 |
1988年 | 23篇 |
1987年 | 25篇 |
1986年 | 13篇 |
1985年 | 14篇 |
1984年 | 10篇 |
1983年 | 10篇 |
1982年 | 9篇 |
1981年 | 8篇 |
1979年 | 14篇 |
1978年 | 8篇 |
1973年 | 9篇 |
1972年 | 6篇 |
1971年 | 9篇 |
1968年 | 5篇 |
排序方式: 共有7406条查询结果,搜索用时 10 毫秒
51.
Yixian Liao Yiming Guo Sumei Li Lei Wang Yongmei Tang Tianmiao Li Weihao Chen Guohua Zhong Gaopeng Song 《Bioorganic & medicinal chemistry letters》2018,28(7):1188-1193
This paper describes our medicinal chemistry efforts on 7-(cyclopentyloxy)-6-methoxy1,2,3,4-tetrahydroisoquinoline scaffold: design, synthesis and biological evaluation using conformational restriction approach and bioisosteric replacement strategy. Biological data revealed that the majority of the synthesized compounds of this series displayed moderate to potent inhibitory activity against PDE4B and strong inhibition of LPS-induced TNFα release. Among them, compound 19 exhibited the strongest inhibition against PDE4B with an IC50 of 0.88?µM and 21 times more potent selectivity toward PDE4B over PDE4D when compared to rolipram. A primary structure-activity relationship study showed that the attachment of CH3O group or CF3O group to the phenyl ring at the para-position was helpful to enhance the inhibitory activity against PDE4B. Moreover, sulfonamide group played a key role in improving the inhibitory activity against PDE4B and subtype selectivity. In addition, the attachment of the additional rigid substituents at the C-3 position of 1,2,3,4-tetrahydroisoquinoline ring was favored to subtype selectivity, which was consistent well with the observed docking simulation. 相似文献
52.
Functional Characterization of 14 Pht1 Family Genes in Yeast and Their Expressions in Response to Nutrient Starvation in Soybean 总被引:1,自引:0,他引:1
Lu Qin Yongxiang Guo Liyu Chen Ruikang Liang Mian Gu Guohua Xu Jing Zhao Thomas Walk Hong Liao 《PloS one》2012,7(10)
Background
Phosphorus (P) is essential for plant growth and development. Phosphate (Pi) transporter genes in the Pht1 family play important roles in Pi uptake and translocation in plants. Although Pht1 family genes have been well studied in model plants, little is known about their functions in soybean, an important legume crop worldwide.Principal Findings
We identified and isolated a complete set of 14 Pi transporter genes (GmPT1-14) in the soybean genome and categorized them into two subfamilies based on phylogenetic analysis. Then, an experiment to elucidate Pi transport activity of the GmPTs was carried out using a yeast mutant defective in high-affinity Pi transport. Results showed that 12 of the 14 GmPTs were able to complement Pi uptake of the yeast mutant with Km values ranging from 25.7 to 116.3 µM, demonstrating that most of the GmPTs are high-affinity Pi transporters. Further results from qRT-PCR showed that the expressions of the 14 GmPTs differed not only in response to P availability in different tissues, but also to other nutrient stresses, including N, K and Fe deficiency, suggesting that besides functioning in Pi uptake and translocation, GmPTs might be involved in synergistic regulation of mineral nutrient homeostasis in soybean.Conclusions
The comprehensive analysis of Pi transporter function in yeast and expression responses to nutrition starvation of Pht1 family genes in soybean revealed their involvement in other nutrient homeostasis besides P, which could help to better understand the regulation network among ion homeostasis in plants. 相似文献53.
54.
Jing Zhang Ga Liao Chang Liu Lei Sun Yanyou Liu Yuhui Wang Zhou Jiang Zhengrong Wang 《Molecular biology reports》2011,38(1):349-354
Many reports have shown that the biologic rhythm could be altered due to mutations of circadian gene hClock or hPeriod, and
the mutations of circadian genes have some relationship with psychosis according to recent studies. A preliminary study has
been conducted to examine wether the T3111C single nucleotide polymorphism of the hClock gene or the length polymorphism of
the hPer3 gene is associated with the development of schizophrenia. The samples from schizophrenics (n = 148, male: 57.4%, female: 42.6%) and normal controls (n = 199, male: 59.3%, female: 40.7%) were examined. Allele frequencies of T3111C SNP of hClock were significantly different
between schizophrenics and controls (χ2 = 19.738, P < 0.05). Schizophrenics had a significantly higher frequency of the C allele compared with controls (OR = 2.613, 95% CI = 1.693–4.034).
On the other hand, there is no significant difference of allele frequencies of 18 exon of hper3 between schizophrenics and controls (χ2 = 0.192, P > 0.05). Our results suggest that the T3111C (RS1801260) polymorphism of hClock gene is associated with schizophrenia, but
it seems that the length polymorphism of 18 exon of hPer3 may not be associated with schizophrenia. It is important to address
of the relationship between circadian gene polymorphisms and dopamine functions in further study. 相似文献
55.
Elena Kurenova Deniz Ucar Jianqun Liao Michael Yemma Priyanka Gogate Wiam Bshara 《Cell cycle (Georgetown, Tex.)》2014,13(16):2542-2553
Melanoma has the highest mortality rate of all skin cancers and a major cause of treatment failure is drug resistance. Tumors heterogeneity requires novel therapeutic strategies and new drugs targeting multiple pathways. One of the new approaches is targeting the scaffolding function of tumor related proteins such as focal adhesion kinase (FAK). FAK is overexpressed in most solid tumors and is involved in multiple protein-protein interactions critical for tumor cell survival, tumor neovascularization, progression and metastasis. In this study, we investigated the anticancer activity of the FAK scaffold inhibitor C4, targeted to the FAK-VEGFR-3 complex, against melanomas. We compared C4 inhibitory effects in BRAF mutant vs BRAF wild type melanomas. C4 effectively caused melanoma tumor regression in vivo, when administered alone and sensitized tumors to chemotherapy. The most dramatic effect of C4 was related to reduction of vasculature of both BRAF wild type and V600E mutant xenograft tumors. The in vivo effects of C4 were assessed in xenograft models using non-invasive multimodality imaging in conjunction with histologic and molecular biology methods. C4 inhibited cell viability, adhesion and motility of melanoma and endothelial cells, specifically blocked phosphorylation of VEGFR-3 and FAK and disrupted their complexes. Specificity of in vivo effects for C4 were confirmed by a decrease in tumor FAK and VEGFR-3 phosphorylation, reduction of vasculogenesis and reduced blood flow. Our collective observations provide evidence that a small molecule inhibitor targeted to the FAK protein-protein interaction site successfully inhibits melanoma growth through dual targeting of tumor and endothelial cells and is effective against both BRAF wild type and mutant melanomas. 相似文献
56.
Genevieve G. A. Fouda Joshua D. Amos Andrew B. Wilks Justin Pollara Caroline A. Ray Anjali Chand Erika L. Kunz Brooke E. Liebl Kaylan Whitaker Angela Carville Shannon Smith Lisa Colvin David J. Pickup Herman F. Staats Glenn Overman Krissey Eutsey-Lloyd Robert Parks Haiyan Chen Celia LaBranche Susan Barnett Georgia D. Tomaras Guido Ferrari David C. Montefiori Hua-Xin Liao Norman L. Letvin Barton F. Haynes Sallie R. Permar 《Journal of virology》2013,87(12):6986-6999
We previously demonstrated that vaccination of lactating rhesus monkeys with a DNA prime/vector boost strategy induces strong T-cell responses but limited envelope (Env)-specific humoral responses in breast milk. To improve vaccine-elicited antibody responses in milk, hormone-induced lactating rhesus monkeys were vaccinated with a transmitted/founder (T/F) HIV Env immunogen in a prime-boost strategy modeled after the moderately protective RV144 HIV vaccine. Lactating rhesus monkeys were intramuscularly primed with either recombinant DNA (n = 4) or modified vaccinia virus Ankara (MVA) poxvirus vector (n = 4) expressing the T/F HIV Env C.1086 and then boosted twice intramuscularly with C.1086 gp120 and the adjuvant MF59. The vaccines induced Env-binding IgG and IgA as well as neutralizing and antibody-dependent cellular cytotoxicity (ADCC) responses in plasma and milk of most vaccinated animals. Importantly, plasma neutralization titers against clade C HIV variants MW965 (P = 0.03) and CAP45 (P = 0.04) were significantly higher in MVA-primed than in DNA-primed animals. The superior systemic prime-boost regimen was then compared to a mucosal-boost regimen, in which animals were boosted twice intranasally with C.1086 gp120 and the TLR 7/8 agonist R848 following the same systemic prime. While the systemic and mucosal vaccine regimens elicited comparable levels of Env-binding IgG antibodies, mucosal immunization induced significantly stronger Env-binding IgA responses in milk (P = 0.03). However, the mucosal regimen was not as potent at inducing functional IgG responses. This study shows that systemic MVA prime followed by either intranasal or systemic protein boosts can elicit strong humoral responses in breast milk and may be a useful strategy to interrupt postnatal HIV-1 transmission. 相似文献
57.
Climate‐driven speedup of alpine treeline forest growth in the Tianshan Mountains,Northwestern China 下载免费PDF全文
Forest growth is sensitive to interannual climatic change in the alpine treeline ecotone (ATE). Whether the alpine treeline ecotone shares a similar pattern of forest growth with lower elevational closed forest belt (CFB) under changing climate remains unclear. Here, we reported an unprecedented acceleration of Picea schrenkiana forest growth since 1960s in the ATE of Tianshan Mountains, northwestern China by a stand‐total sampling along six altitudinal transects with three plots in each transect: one from the ATE between the treeline and the forest line, and the other two from the CFB. All the sampled P. schrenkiana forest patches show a higher growth speed after 1960 and, comparatively, forest growth in the CFB has sped up much slower than that in the ATE. The speedup of forest growth at the ATE is mainly accounted for by climate factors, with increasing temperature suggested to be the primary driver. Stronger water deficit as well as more competition within the CFB might have restricted forest growth there more than that within the ATE, implying biotic factors were also significant for the accelerated forest growth in the ATE, which should be excluded from simulations and predictions of warming‐induced treeline dynamics. 相似文献
58.
59.
Nour Makarem Jacob Paul Elsa-Grace V. Giardina Ming Liao 《Chronobiology international》2020,37(5):673-685
ABSTRACT Chronotype reflects time of day preferences for performing daily activities. Previous research within Asian and European cohorts indicates evening chronotype is associated with elevated cardiometabolic risk. However, evidence is limited from population-based US cohorts, particularly among women in whom evening chronotype prevalence may become higher after middle-age, coinciding with life stages associated with higher cardiovascular disease (CVD) risk. This cross-sectional study evaluated associations of chronotype with overall cardiovascular health (CVH), health behaviors, and cardiometabolic risk factors among 506 women (mean age = 37 ± 16y, 62% racial/ethnic minority) in the American Heart Association (AHA)’s Go Red for Women Strategically-Focused Research Network cohort at Columbia University (New York City, NY, USA). Chronotype was assessed using the validated Morningness-Eveningness Questionnaire (MEQ) and categorized as “evening”, “intermediate”, and “morning” chronotypes. Health behaviors (diet, physical activity, and sleep) were assessed using validated questionnaires. Anthropometrics, clinical blood pressure, and blood biomarkers were assessed at the clinic visit. CVH was evaluated using the AHA Life’s Simple 7 (LS7) metrics; LS7 scores of 0–8 and 9–14 were considered indicative of poor and moderate-to-high CVH, respectively. Linear and logistic regression models adjusted for age, race/ethnicity, education, health insurance, and menopausal status were used to examine associations of MEQ scores and chronotype categories with overall CVH, clinical cardiometabolic risk factors, and health behaviors. Overall, 13% of women identified as evening chronotypes, while 55% and 32% reported being intermediate and morning types. In linear models, higher MEQ scores were associated with higher AHA LS7 scores (β(SE) = 0.02(0.01); p = .014), indicative of more favorable CVH, and with health behaviors not included in the LS7. Higher MEQ scores were also associated with lower Pittsburgh Sleep Quality Index, i.e. better sleep quality, (β(SE) = ?0.07(0.02), p < .0001), lower insomnia severity (β(SE) = ?0.14(0.01), p < .0001), shorter time to fall asleep (β(SE) = ?0.28(0.14), p = .044), and less sedentary time (β(SE) = ?0.11(0.03), p = .001). In logistic regression models, evening chronotype, compared to intermediate/morning type, was associated with higher odds of having poor CVH (OR(95%CI):2.41(1.20–4.85)), not meeting AHA diet (OR(95%CI):2.89(1.59–5.23)) and physical activity guidelines (OR(95%CI):1.78(1.03–3.07)), and having short sleep (OR(95%CI):2.15(1.24–3.73)) or insomnia (OR(95%CI):2.69(1.53–4.75)). The evening type compared to morning type was also associated with being a current smoker (OR(95%CI):2.14(1.02–4.52)) and having poor sleep quality (OR(95%CI:2.35(1.27–4.37)) and long sleep onset latency (OR(95%CI:1.89(1.00–3.56)). In our cohort of women, evening chronotype was related to poor CVH, likely driven by its influence on health behaviors. These findings, although warranting confirmation prospectively in other populations, suggest chronotype is an important factor to consider and possibly target when designing lifestyle interventions for CVD prevention. 相似文献
60.
Pengju Zhang Jun Wang Hongyan Lang Weixia Wang Xiaohui Liu Haiyan Liu Chengcheng Tan Xintao Li Yumin Zhao Xinghong Wu 《Journal of cellular biochemistry》2019,120(5):8466-8474
MicroRNA-205 (miR-205) is involved in various physiological and pathological processes, but its biological function in follicular atresia remains unclear. In this study, we investigated miR-205 expression in mouse granulosa cells (mGCs) and analyzed its functions in primary mGCs by performing a series of in vitro experiments. Quantitative real-time polymerase chain reaction showed that miR-205 expression was significantly higher in early atretic follicles and progressively atretic follicles than in healthy follicles. miR-205 overexpression in mGCs significantly promoted apoptosis and caspase-3/9 activities, as well as inhibited estrogen (E2) release and cytochrome P450 family 19 subfamily A polypeptide 1 (CYP19A1, a key gene in E2 production) expression. Bioinformatics and luciferase reporter assays revealed that the gene encoding cyclic AMP response element (CRE)-binding protein 1 (CREB1) was a direct target of miR-205 in mGCs. CREB1 upregulation partially rescued the effects of miR-205 on apoptosis, caspase-3/9 activities, E2 production, and CYP19A1 expression on mGCs. These results indicate that miR-205 might play an important role in ovarian follicular development and provide new insights into follicular atresia 相似文献