全文获取类型
收费全文 | 5187篇 |
免费 | 340篇 |
国内免费 | 15篇 |
出版年
2023年 | 17篇 |
2022年 | 45篇 |
2021年 | 116篇 |
2020年 | 88篇 |
2019年 | 88篇 |
2018年 | 140篇 |
2017年 | 120篇 |
2016年 | 172篇 |
2015年 | 282篇 |
2014年 | 328篇 |
2013年 | 363篇 |
2012年 | 453篇 |
2011年 | 442篇 |
2010年 | 262篇 |
2009年 | 214篇 |
2008年 | 315篇 |
2007年 | 273篇 |
2006年 | 227篇 |
2005年 | 189篇 |
2004年 | 209篇 |
2003年 | 169篇 |
2002年 | 126篇 |
2001年 | 76篇 |
2000年 | 93篇 |
1999年 | 65篇 |
1998年 | 41篇 |
1997年 | 38篇 |
1996年 | 23篇 |
1995年 | 23篇 |
1993年 | 16篇 |
1992年 | 33篇 |
1991年 | 29篇 |
1990年 | 40篇 |
1989年 | 23篇 |
1988年 | 37篇 |
1987年 | 31篇 |
1986年 | 19篇 |
1985年 | 23篇 |
1984年 | 20篇 |
1983年 | 14篇 |
1978年 | 17篇 |
1976年 | 17篇 |
1975年 | 16篇 |
1974年 | 20篇 |
1973年 | 18篇 |
1972年 | 16篇 |
1971年 | 16篇 |
1970年 | 17篇 |
1969年 | 13篇 |
1968年 | 16篇 |
排序方式: 共有5542条查询结果,搜索用时 15 毫秒
131.
Sung Tae Kim Takafumi Tasaki Adriana Zakrzewska Young Dong Yoo Ki Sa Sung Su-Hyeon Kim Hyunjoo Cha-Molstad Joonsung Hwang Kyoung A Kim Bo Yeon Kim Yong Tae Kwon 《Autophagy》2013,9(7):1100-1103
The N-end rule pathway is a cellular proteolytic system that utilizes specific N-terminal residues as degradation determinants, called N-degrons. N-degrons are recognized and bound by specific recognition components (N-recognins) that mediate polyubiquitination of low-abundance regulators and selective proteolysis through the proteasome. Our earlier work identified UBR4/p600 as one of the N-recognins that promotes N-degron-dependent proteasomal degradation. In this study, we show that UBR4 is associated with cellular cargoes destined to autophagic vacuoles and is degraded by the lysosome. UBR4 loss causes multiple misregulations in autophagic pathways, including an increased formation of LC3 puncta. UBR4-deficient mice die during embryogenesis primarily due to defective vascular development in the yolk sac (YS), wherein UBR4 is associated with a bulk lysosomal degradation system that absorbs maternal proteins from the YS cavity and digests them into amino acids. Our results suggest that UBR4 plays a role not only in selective proteolysis of short-lived regulators through the proteasome, but also bulk degradation through the lysosome. Here, we discuss a possible mechanism of UBR4 as a regulatory component in the delivery of cargoes destined to interact with the autophagic core machinery. 相似文献
132.
Jae Young So Amanda K. Smolarek David M. Salerno Hubert Maehr Milan Uskokovic Fang Liu Nanjoo Suh 《PloS one》2013,8(1)
Background
CD44, a transmembrane glycoprotein, is a major receptor for extracellular proteins involved in invasion and metastasis of human cancers. We have previously demonstrated that the novel Gemini vitamin D analog BXL0124 [1α,25-dihydroxy-20R-21(3-hydroxy-3-deuteromethyl-4,4,4-trideuterobutyl)-23-yne-26,27-hexafluro-cholecalciferol] repressed CD44 expression in MCF10DCIS.com basal-like human breast cancer cells and inhibited MCF10DCIS xenograft tumor growth. In the present study, we investigated potential factors downstream of CD44 and the biological role of CD44 repression by BXL0124 in MCF10DCIS cells.Methods and Findings
The treatment with Gemini vitamin D BXL0124 decreased CD44 protein level, suppressed STAT3 signaling, and inhibited invasion and proliferation of MCF10DCIS cells. The interaction between CD44 and STAT3 was determined by co-immunoprecipitation. CD44 forms a complex with STAT3 and Janus kinase 2 (JAK2) to activate STAT3 signaling, which was inhibited by BXL0124 in MCF10DCIS cells. The role of CD44 in STAT3 signaling and invasion of MCF10DCIS cells was further determined by the knockdown of CD44 using small hairpin RNA in vitro and in vivo. MCF10DCIS cell invasion was markedly decreased by the knockdown of CD44 in vitro. The knockdown of CD44 also significantly decreased mRNA expression levels of invasion markers, matrix metalloproteinases (MMPs) and urokinase plasminogen activator (uPA), in MCF10DCIS cells. In MCF10DCIS xenograft tumors, CD44 knockdown decreased tumor size and weight as well as invasion markers.Conclusions
The present study identifies STAT3 as an important signaling molecule interacting with CD44 and demonstrates the essential role of CD44-STAT3 signaling in breast cancer invasion. It also suggests that repression of CD44-STAT3 signaling is a key molecular mechanism in the inhibition of breast cancer invasion by the Gemini vitamin D analog BXL0124. 相似文献133.
Jae Su Kim Jae Young Choi Joo Hyun Lee Jong Bin Park Zhenli Fu Qin Liu Xueying Tao Byung Rae Jin Margaret Skinner Bruce L. Parker Yeon Ho Je 《PloS one》2013,8(4)
Insect-killing (entomopathogenic) fungi have high potential for controlling agriculturally harmful pests. However, their pathogenicity is slow, and this is one reason for their poor acceptance as a fungal insecticide. The expression of bumblebee, Bombus ignitus, venom serine protease (VSP) by Beauveria bassiana (ERL1170) induced melanization of yellow spotted longicorn beetles (Psacothea hilaris) as an over-reactive immune response, and caused substantially earlier mortality in beet armyworm (Spodopetra exigua) larvae when compared to the wild type. No fungal outgrowth or sporulation was observed on the melanized insects, thus suggesting a self-restriction of the dispersal of the genetically modified fungus in the environment. The research is the first use of a multi-functional bumblebee VSP to significantly increase the speed of fungal pathogenicity, while minimizing the dispersal of the fungal transformant in the environment. 相似文献
134.
135.
Jin-Ha Yoon Sung-Kyung Kim Ho-June Choi Soo-In Choi So-Youn Cha Sang-Baek Koh Hee-Taik Kang Song Vogue Ahn 《PloS one》2013,8(10)
Background
This study evaluated the relation between adiponectin and atherosclerosis in both genders, and investigated whether adiponectin provides useful additional information for assessing the risk of atherosclerosis.Methods
We measured serum adiponectin levels and other cardiovascular risk factors in 1033 subjects (454 men, 579 women) from the Korean Genomic Rural Cohort study. Carotid intima–media-thickness (CIMT) was used as measure of atherosclerosis. Odds ratios (ORs) with 95% confidence intervals (95% CI) were calculated using multiple logistic regression, and receiver operating characteristic curves (ROC), the category-free net reclassification improvement (NRI) and integrated discrimination improvement (IDI) were calculated.Results
After adjustment for conventional cardiovascular risk factors, such as age, waist circumference, smoking history, low-density and high-density lipoprotein cholesterol, triglycerides, systolic blood pressure and insulin resistance, the ORs (95%CI) of the third tertile adiponectin group were 0.42 (0.25–0.72) in men and 0.47 (0.29–0.75) in women. The area under the curve (AUC) on the ROC analysis increased significantly by 0.025 in men and 0.022 in women when adiponectin was added to the logistic model of conventional cardiovascular risk factors (AUC in men: 0.655 to 0.680, p = 0.038; AUC in women: 0.654 to 0.676, p = 0.041). The NRI was 0.32 (95%CI: 0.13–0.50, p<0.001), and the IDI was 0.03 (95%CI: 0.01–0.04, p<0.001) for men. For women, the category-free NRI was 0.18 (95%CI: 0.02–0.34, p = 0.031) and the IDI was 0.003 (95%CI: −0.002–0.008, p = 0.189).Conclusion
Adiponectin and atherosclerosis were significantly related in both genders, and these relationships were independent of conventional cardiovascular risk factors. Furthermore, adiponectin provided additional information to conventional cardiovascular risk factors regarding the risk of atherosclerosis. 相似文献136.
Ok Yeon Jeong You Hee Sang Lee Song Hee Sung Ho Joong Kang Hee-Gyoo Hyun Sung Hee 《Indian journal of microbiology》2020,60(2):206-213
Indian Journal of Microbiology - For bacteria sampling studies, various collection methods have been used to identify bacteria. To obtain accurate information about bacteria, high quality samples... 相似文献
137.
Migyeong Jo Sanghwan Ko Bora Hwang Sung-Won Min Ji Yeon Ha Ji Chul Lee Se-Eun Jang Sang Taek Jung 《Biotechnology and bioengineering》2020,117(8):i-i
The immunoglobulin G (IgG) molecule has a long circulating serum half-life (~3 weeks) through pH- dependent FcRn binding-mediated recycling. To hijack the intracellular trafficking and recycling mechanism of IgG as a way to extend serum persistence of non-antibody therapeutic proteins, we have evolved the ectodomain of a low-affinity human FcγRIIa for enhanced binding to the lower hinge and upper CH2 region of IgG, which is very far from the FcRn binding site (CH2–CH3 interface). High-throughput library screening enabled isolation of an FcγRIIa variant (2A45.1) with 32-fold increased binding affinity to human IgG1 Fc (equilibrium dissociation constant: 9.04 × 10−7 M for wild type FcγRIIa and 2.82 × 10−8 M for 2A45.1) and significantly improved affinity to mouse serum IgG compared to wild type human FcγRIIa. The in vivo pharmacokinetic profile of PD-L1 fused with engineered FcγRIIa (PD-L1–2A45.1) was compared with that of PD-L1 fused with wild type FcγRIIa (PD-L1–wild type FcγRIIa) and human PD-L1 in mice. PD-L1–2A45.1 showed 11.7- and 9.7-fold prolonged circulating half-life (t1/2) compared to PD-L1 when administered intravenously and intraperitoneally, respectively. In addition, the AUCinf of PD-L1–2A45.1 was two-fold higher compared to that of PD-L1–wild type FcγRIIa. These results demonstrate that engineered FcγRIIa fusion offers a novel and successful strategy for prolonging serum half-life of therapeutic proteins. 相似文献
138.
139.
Jeyoun Jang Minhui Cho Hae-Ri Lee Kiweon Cha Jeong-Hoon Chun Kee-Jong Hong Jungchan Park Gi-eun Rhie 《Biochimica et Biophysica Acta (BBA)/General Subjects》2013
Background
The poly-γ-d-glutamic acid (PGA) capsule, a major virulence factor of Bacillus anthracis, protects bacilli from immune surveillance and allows its unimpeded growth in the host. Recently, the importance of the PGA in the pathogenesis of anthrax infection has been reported. The PGA capsule is associated with lethal toxin (LT) in the blood of experimentally infected animals and enhances the cytotoxicity of LT.Methods
To investigate the role of anti-PGA Abs on progression of anthrax infection, two mouse anti-PGA mAbs with Kd values of 0.8 μM and 2.6 μM respectively were produced and in silico three dimensional (3D) models of mAbs with their cognitive PGA antigen complex were analyzed.Results
Anti-PGA mAbs specifically bound encapsulated B. anthracis H9401 and showed opsonophagocytosis activity against the bacteria with complement. The enhancement effect of PGA on LT-mediated cytotoxicity was confirmed ex vivo using mouse bone marrow-derived macrophages and was effectively inhibited by anti-PGA mAb. Passive immunization of mAb completely protected mice from PGA-enhanced LT toxicity and partially rescued mice from anthrax spore challenges. 3D structure models of these mAbs and PGA complex support specific interactions between CDR and cognitive PGA. These results indicate that mouse mAb against PGA capsule prevents the progress of anthrax disease not only by eliminating the vegetative form of encapsulated B. anthracis but also by inhibiting the enhanced cytotoxic activity of LT by PGA through specific binding with PGA capsule antigen.General significance
Our results suggest a potential role for PGA antibodies in preventing and treating anthrax infection. 相似文献140.
Pitna Kim Jin Hee Park Chang Soon Choi Inah Choi So Hyun Joo Min Kyoung Kim Soo Young Kim Ki Chan Kim Seung Hwa Park Kyoung Ja Kwon Jongmin Lee Seol-Heui Han Jong Hoon Ryu Jae Hoon Cheong Jung Yeol Han Ki Narm Ko Chan Young Shin 《Neurochemical research》2013,38(3):620-631
Prenatal exposure to alcohol has consistently been associated with adverse effects on neurodevelopment, which is collectively called fetal alcohol spectrum disorder (FASD). Increasing evidence suggest that prenatal exposure to alcohol increases the risk of developing attention deficit/hyperactivity disorder-like behavior in human. In this study, we investigated the behavioral effects of prenatal exposure to EtOH in offspring mice and rats focusing on hyperactivity and impulsivity. We also examined changes in dopamine transporter and MeCP2 expression, which may underlie as a key neurobiological and epigenetic determinant in FASD and hyperactive, inattentive and impulsive behaviors. Mouse or rat offspring born from dam exposed to alcohol during pregnancy (EtOH group) showed hyper locomotive activity, attention deficit and impulsivity. EtOH group also showed increased dopamine transporter and norepinephrine transporter level compared to control group in the prefrontal cortex and striatum. Prenatal exposure to EtOH also significantly decreased the expression of MeCP2 in both prefrontal cortex and striatum. These results suggest that prenatal exposure to EtOH induces hyperactive, inattentive and impulsive behaviors in rodent offspring that might be related to global epigenetic changes as well as aberration in catecholamine neurotransmitter transporter system. 相似文献