全文获取类型
收费全文 | 1169篇 |
免费 | 80篇 |
国内免费 | 2篇 |
出版年
2023年 | 12篇 |
2022年 | 13篇 |
2021年 | 40篇 |
2020年 | 36篇 |
2019年 | 31篇 |
2018年 | 53篇 |
2017年 | 43篇 |
2016年 | 63篇 |
2015年 | 72篇 |
2014年 | 95篇 |
2013年 | 98篇 |
2012年 | 115篇 |
2011年 | 88篇 |
2010年 | 54篇 |
2009年 | 49篇 |
2008年 | 42篇 |
2007年 | 45篇 |
2006年 | 46篇 |
2005年 | 35篇 |
2004年 | 40篇 |
2003年 | 12篇 |
2002年 | 22篇 |
2001年 | 7篇 |
2000年 | 7篇 |
1999年 | 11篇 |
1998年 | 7篇 |
1997年 | 6篇 |
1996年 | 6篇 |
1995年 | 3篇 |
1994年 | 4篇 |
1993年 | 5篇 |
1992年 | 5篇 |
1991年 | 3篇 |
1990年 | 4篇 |
1989年 | 6篇 |
1988年 | 4篇 |
1987年 | 5篇 |
1986年 | 5篇 |
1985年 | 10篇 |
1983年 | 3篇 |
1982年 | 4篇 |
1980年 | 3篇 |
1979年 | 6篇 |
1978年 | 3篇 |
1976年 | 6篇 |
1974年 | 4篇 |
1973年 | 5篇 |
1970年 | 2篇 |
1967年 | 2篇 |
1966年 | 2篇 |
排序方式: 共有1251条查询结果,搜索用时 15 毫秒
1.
Genome-wide expression profiling has revolutionized biomedical research; vast amounts of expression data from numerous studies of many diseases are now available. Making the best use of this resource in order to better understand disease processes and treatment remains an open challenge. In particular, disease biomarkers detected in case–control studies suffer from low reliability and are only weakly reproducible. Here, we present a systematic integrative analysis methodology to overcome these shortcomings. We assembled and manually curated more than 14 000 expression profiles spanning 48 diseases and 18 expression platforms. We show that when studying a particular disease, judicious utilization of profiles from other diseases and information on disease hierarchy improves classification quality, avoids overoptimistic evaluation of that quality, and enhances disease-specific biomarker discovery. This approach yielded specific biomarkers for 24 of the analyzed diseases. We demonstrate how to combine these biomarkers with large-scale interaction, mutation and drug target data, forming a highly valuable disease summary that suggests novel directions in disease understanding and drug repurposing. Our analysis also estimates the number of samples required to reach a desired level of biomarker stability. This methodology can greatly improve the exploitation of the mountain of expression profiles for better disease analysis. 相似文献
2.
3.
Abhishek Chatterjee Celia Caballero-Franco Dannika Bakker Stephanie Totten Armando Jardim 《The Journal of biological chemistry》2015,290(42):25579-25594
Enterohemorrhagic Escherichia coli is a causative agent of gastrointestinal and diarrheal diseases. Pathogenesis associated with enterohemorrhagic E. coli involves direct delivery of virulence factors from the bacteria into epithelial cell cytosol via a syringe-like organelle known as the type III secretion system. The type III secretion system protein EspD is a critical factor required for formation of a translocation pore on the host cell membrane. Here, we show that recombinant EspD spontaneously integrates into large unilamellar vesicle (LUV) lipid bilayers; however, pore formation required incorporation of anionic phospholipids such as phosphatidylserine and an acidic pH. Leakage assays performed with fluorescent dextrans confirmed that EspD formed a structure with an inner diameter of ∼2.5 nm. Protease mapping indicated that the two transmembrane helical hairpin of EspD penetrated the lipid layer positioning the N- and C-terminal domains on the extralumenal surface of LUVs. Finally, a combination of glutaraldehyde cross-linking and rate zonal centrifugation suggested that EspD in LUV membranes forms an ∼280–320-kDa oligomeric structure consisting of ∼6–7 subunits. 相似文献
4.
5.
G. N. Zholtkevych K. V. Nosov Yu. G. Bespalov L. I. Rak M. Abhishek E. V. Vysotskaya 《Acta biotheoretica》2018,66(3):177-199
The state-of-art research in the field of life’s organization confronts the need to investigate a number of interacting components, their properties and conditions of sustainable behaviour within a natural system. In biology, ecology and life sciences, the performance of such stable system is usually related to homeostasis, a property of the system to actively regulate its state within a certain allowable limits. In our previous work, we proposed a deterministic model for systems’ homeostasis. The model was based on dynamical system’s theory and pairwise relationships of competition, amensalism and antagonism taken from theoretical biology and ecology. However, the present paper proposes a different dimension to our previous results based on the same model. In this paper, we introduce the influence of inter-component relationships in a system, wherein the impact is characterized by direction (neutral, positive, or negative) as well as its (absolute) value, or strength. This makes the model stochastic which, in our opinion, is more consistent with real-world elements affected by various random factors. The case study includes two examples from areas of hydrobiology and medicine. The models acquired for these cases enabled us to propose a convincing explanation for corresponding phenomena identified by different types of natural systems. 相似文献
6.
Sougata Ghosh Piyush More Abhishek Derle Ajay B. Patil Pramod Markad Adersh Asok Navanath Kumbhar Mahemud L. Shaikh Boppana Ramanamurthy Vaishali S. Shinde Dilip D. Dhavale Balu A. Chopade 《PloS one》2014,9(9)
Diabetes mellitus is a multifactorial metabolic disease characterized by post-prandial hyperglycemia (PPHG). α-amylase and α-glucosidase inhibitors aim to explore novel therapeutic agents. Herein we report the promises of Dioscorea bulbifera and its bioactive principle, diosgenin as novel α-amylase and α-glucosidase inhibitor. Among petroleum ether, ethyl acetate, methanol and 70% ethanol (v/v) extracts of bulbs of D. bulbifera, ethyl acetate extract showed highest inhibition upto 72.06 ± 0.51% and 82.64 ± 2.32% against α-amylase and α-glucosidase respectively. GC-TOF-MS analysis of ethyl acetate extract indicated presence of high diosgenin content. Diosgenin was isolated and identified by FTIR, 1H NMR and 13C NMR and confirmed by HPLC which showed an α-amylase and α-glucosidase inhibition upto 70.94 ± 1.24% and 81.71 ± 3.39%, respectively. Kinetic studies confirmed the uncompetitive mode of binding of diosgenin to α-amylase indicated by lowering of both Km and Vm. Interaction studies revealed the quenching of intrinsic fluorescence of α-amylase in presence of diosgenin. Similarly, circular dichroism spectrometry showed diminished negative humped peaks at 208 nm and 222 nm. Molecular docking indicated hydrogen bonding between carboxyl group of Asp300, while hydrophobic interactions between Tyr62, Trp58, Trp59, Val163, His305 and Gln63 residues of α-amylase. Diosgenin interacted with two catalytic residues (Asp352 and Glu411) from α-glucosidase. This is the first report of its kind that provides an intense scientific rationale for use of diosgenin as novel drug candidate for type II diabetes mellitus. 相似文献
7.
Abhishek Sharma Satyawati Sharma Aditya Mittal Satya Narayan Naik 《Annals of microbiology》2014,64(2):515-520
The development of biofriendly and economical alternatives to chemical pesticides is a globally important scientific challenge. In this work, Karanja-based media conditions were optimized for obtaining high production of biomass and spores of a biocontrol agent, the entomopathogenic fungus Paecilomyces lilacinus 6029, using a two-step statistical approach coupled with rigorous experimentation. In the first step, non-edible Karanja cake was screened out as a major substrate from other oil cakes. In the second step, biomass production was maximized by applying response surface methodology to experimental variations in key physico-chemical factors: carbon/nitrogen (C/N) ratio and pH. This approach eventually predicted a maximum biomass production of 10.559 g/l with a medium having a C/N ratio of 35.88 and pH 5.9. An experimental production of 10.529 g/l biomass was obtained. The remarkable agreement between the predicted and the experimentally obtained biomass confirm the validity of the approach utilized to maximize production of P. lilacinus. 相似文献
8.
9.
Somdev Tyagi Kimio Inoue Amar Nath 《Biochimica et Biophysica Acta (BBA)/General Subjects》1978,539(1):125-134
Subtle changes in Mössbauer parameters are observed while going from methyl- to ethyl- to adenosylcobalamin, and also when the ‘base’ is detached from the cobalt. The observation of these changes demonstrates that the Co-C bond, among others, remains intact after the Auger event, accompanying the electron-capture decay of the cobalt-57.The differences between ethylcobalamin and the other two organocobalamins in the magnitude of the quadrupole splittings have been interpreted on the basis of the σ-donating tendency of the organic moiety and the CoC bond length. The latter is presumably determined by the steric hindrance offered to the group in approaching the cobalt atom.The ethyl- and adenosylcobalamins in their ‘base-off’ form exhibit a larger quadrupole splitting than the corresponding ‘base-on’ form. In the ‘base-off’ form, the cobalt atom is perhaps raised above the mean plane of the four equatorial nitrogen atoms of the corrin ring, which may result in the diminution of the delocalization of the 3dπ electron density. The higher population of dπ orbitals and the enhanced metallic character of the dz2, resulting from shrink-age of the CoC bond length, enhances the magnitude of the quadrupole splitting. 相似文献
10.
Anshuman Mishra Sheikh Nizamuddin Geethika Arekatla Satya Prakash Hemlata Dewangan Abishai Dominic Abhishek Mishra Digumarthi V. S. Sudhakar Narasimha R. Parine Nitin C. Tupperwar Kumarasamy Thangaraj 《PloS one》2015,10(5)
BackgroundVisceral leishmaniasis (VL) is a multifactorial disease, where the host genetics play a significant role in determining the disease outcome. The immunological role of anti-inflammatory cytokine, Interleukin 10 (IL10), has been well-documented in parasite infections and considered as a key regulatory cytokine for VL. Although VL patients in India display high level of IL10 in blood serum, no genetic study has been conducted to assess the VL susceptibility / resistance. Therefore, the aim of this study is to investigate the role of IL10 variations in Indian VL; and to estimate the distribution of disease associated allele in diverse Indian populations.MethodologyAll the exons and exon-intron boundaries of IL10 were sequenced in 184 VL patients along with 172 ethnically matched controls from VL endemic region of India.