全文获取类型
收费全文 | 2517篇 |
免费 | 165篇 |
国内免费 | 2篇 |
专业分类
2684篇 |
出版年
2023年 | 17篇 |
2022年 | 37篇 |
2021年 | 57篇 |
2020年 | 38篇 |
2019年 | 40篇 |
2018年 | 50篇 |
2017年 | 52篇 |
2016年 | 60篇 |
2015年 | 101篇 |
2014年 | 107篇 |
2013年 | 158篇 |
2012年 | 178篇 |
2011年 | 180篇 |
2010年 | 104篇 |
2009年 | 107篇 |
2008年 | 126篇 |
2007年 | 130篇 |
2006年 | 106篇 |
2005年 | 74篇 |
2004年 | 81篇 |
2003年 | 61篇 |
2002年 | 51篇 |
2001年 | 57篇 |
2000年 | 53篇 |
1999年 | 43篇 |
1998年 | 20篇 |
1996年 | 24篇 |
1995年 | 20篇 |
1994年 | 16篇 |
1993年 | 17篇 |
1992年 | 23篇 |
1991年 | 27篇 |
1990年 | 29篇 |
1989年 | 20篇 |
1988年 | 36篇 |
1987年 | 35篇 |
1986年 | 24篇 |
1985年 | 27篇 |
1984年 | 19篇 |
1983年 | 19篇 |
1982年 | 19篇 |
1981年 | 15篇 |
1980年 | 18篇 |
1979年 | 26篇 |
1978年 | 15篇 |
1977年 | 21篇 |
1975年 | 13篇 |
1974年 | 16篇 |
1973年 | 14篇 |
1972年 | 12篇 |
排序方式: 共有2684条查询结果,搜索用时 15 毫秒
941.
942.
943.
944.
Vaibhav Kalamkar Mamata Joshi Varsha Borkar Sudha Srivastava Meena Kanyalkar 《Bioorganic & medicinal chemistry》2013,21(21):6753-6762
The development of novel antifungal agents with high susceptibility and increased potency can be achieved by increasing their overall lipophilicity. To enhance the lipophilicity of voriconazole, a second generation azole antifungal agent, we have synthesized its carboxylic acid ester analogues, namely p-methoxybenzoate (Vpmb), toluate (Vtol), benzoate (Vbz) and p-nitrobenzoate (Vpnb). The intermolecular interactions of these analogues with model membrane have been investigated using nuclear magnetic resonance (NMR) and differential scanning calorimetric (DSC) techniques. The results indicate varying degree of changes in the membrane bilayer’s structural architecture and physico-chemical characteristics which possibly can be correlated with the antifungal effects via fungal membrane. Rapid metabolite profiling of chemical entities using cell preparations is one of the most important steps in drug discovery. We have evaluated the effect of synthesized analogues on Candida albicans. The method involves real time 1H NMR measurement of intact cells monitoring NMR signals from fungal metabolites which gives Metabolic End Point (MEP). This is then compared with Minimum Inhibitory Concentration (MIC) determined using conventional methods. Results indicate that one of the synthesized analogues, Vpmb shows reasonably good activity. 相似文献
945.
Brian D. Quinlan Matthew R. Gardner Vinita R. Joshi Jessica J. Chiang Michael Farzan 《The Journal of biological chemistry》2013,288(26):18803-18810
Phage display is a key technology for the identification and maturation of high affinity peptides, antibodies, and other proteins. However, limitations of bacterial expression restrict the range and sensitivity of assays that can be used to evaluate phage-selected variants. To address this problem, selected genes are typically transferred to mammalian expression vectors, a major rate-limiting step in the iterative improvement of peptides and proteins. Here we describe a system that combines phage display and efficient mammalian expression in a single vector, pDQ1. This system permits immediate expression of phage-selected genes as IgG1-Fc fusions in mammalian cells, facilitating the rapid, sensitive characterization of a large number of library outputs for their biochemical and functional properties. We demonstrate the utility of this system by improving the ability of a CD4-mimetic peptide to bind the HIV-1 envelope glycoprotein and neutralize HIV-1 entry. We further improved the potency of the resulting peptide, CD4mim6, by limiting its ability to induce the CD4-bound conformation of the envelope glycoprotein. Thus, CD4mim6 and its variants can be used to investigate the properties of the HIV-1 envelope glycoprotein, and pDQ1 can accelerate the discovery of new peptides and proteins through phage display. 相似文献
946.
Mohd Zaki Salleh Lay Kek Teh Lian Shien Lee Rose Iszati Ismet Ashok Patowary Kandarp Joshi Ayesha Pasha Azni Zain Ahmed Roziah Mohd Janor Ahmad Sazali Hamzah Aishah Adam Khalid Yusoff Boon Peng Hoh Fazleen Haslinda Mohd Hatta Mohamad Izwan Ismail Vinod Scaria Sridhar Sivasubbu 《PloS one》2013,8(8)
Background
With a higher throughput and lower cost in sequencing, second generation sequencing technology has immense potential for translation into clinical practice and in the realization of pharmacogenomics based patient care. The systematic analysis of whole genome sequences to assess patient to patient variability in pharmacokinetics and pharmacodynamics responses towards drugs would be the next step in future medicine in line with the vision of personalizing medicine.Methods
Genomic DNA obtained from a 55 years old, self-declared healthy, anonymous male of Malay descent was sequenced. The subject''s mother died of lung cancer and the father had a history of schizophrenia and deceased at the age of 65 years old. A systematic, intuitive computational workflow/pipeline integrating custom algorithm in tandem with large datasets of variant annotations and gene functions for genetic variations with pharmacogenomics impact was developed. A comprehensive pathway map of drug transport, metabolism and action was used as a template to map non-synonymous variations with potential functional consequences.Principal Findings
Over 3 million known variations and 100,898 novel variations in the Malay genome were identified. Further in-depth pharmacogenetics analysis revealed a total of 607 unique variants in 563 proteins, with the eventual identification of 4 drug transport genes, 2 drug metabolizing enzyme genes and 33 target genes harboring deleterious SNVs involved in pharmacological pathways, which could have a potential role in clinical settings.Conclusions
The current study successfully unravels the potential of personal genome sequencing in understanding the functionally relevant variations with potential influence on drug transport, metabolism and differential therapeutic outcomes. These will be essential for realizing personalized medicine through the use of comprehensive computational pipeline for systematic data mining and analysis. 相似文献947.
Shilo Rosenwasser Robert Fluhr Janak Raj Joshi Noam Leviatan Noa Sela Amotz Hetzroni Haya Friedman 《Plant physiology》2013,163(2):1071-1083
948.
Shibin Ma Vipul Shukla Leilei Fang Karen A. Gould Shantaram S. Joshi Runqing Lu 《The Journal of biological chemistry》2013,288(37):26430-26440
A recent genome-wide SNP association study identified IRF4 as a major susceptibility gene for chronic lymphocytic leukemia (CLL). Moreover, the SNPs located in the 3′ UTR of the IRF4 gene have been linked to a down-regulation of IRF4. However, whether a low level of IRF4 is critical for CLL development remains unclear. New Zealand Black (NZB) mice are a naturally occurring, late-onset mouse model of CLL. To examine the role of a reduced level of IRF4 in CLL development, we generated, through breeding, IRF4 heterozygous mutant mice in the NZB background (NZB IRF4+/−). Our results show that CLL development is accelerated dramatically in the NZB IRF4+/− mice. The average onset of CLL in NZB mice is 12 months, but CLL cells can be detected in NZB IRF4+/− mice at 3 months of age. By 5 months of age, 80% of NZB IRF4+/− mice developed CLL. CLL cells are derived from B1 cells in mice. Interestingly, NZB IRF4+/− B1 cells exhibit prolonged survival, accelerated self-renewal, and defects in differentiation. Although NZB IRF4+/− CLL cells are resistant to apoptosis, high levels of IRF4 inhibit their survival. High levels of IRF4 also reduce the survival of MEC-1 human CLL cells. Our analysis further reveals that high levels of IRF4 suppress Akt activity and can do so without the IRF4 DNA binding domain. Thus, our findings reveal a causal relationship between a low level of IRF4 and the development of CLL and establish IRF4 as a novel regulator in the pathogenesis of CLL. 相似文献
949.
For more than two decades, bioengineered plants have produced protein therapeutics for human and animal use. Almost all proteins produced by other existing systems, including antibodies, vaccines and plasma proteins, have now been manufactured in plants. Considering the limitations of microbial and mammalian reactor-based protein-production technologies and the impending bottleneck in manufacturing capacity, plants are now emerging as an attractive alternative system with which to supply the growing need for protein-based therapeutics. However, full realization of the promise of plant-derived engineered proteins requires that we confront the dual challenges of bioequivalence and product consistency, challenges that are largely related to post-translational protein modifications (PTMs) that are crucial to the structure and function of most eukaryotic proteins. Among the protein PTMs, the foremost challenge for bioactivity and acceptance by the pharmaceutical and biotechnology industries and regulatory agencies is glycosylation. Advances made in recent years that 'humanize' plant glycosylation pathways combined with the discovery of terminal sialic acids (SAs) in plants now make feasible the bioengineering in plants of glycoproteins that have mammalian-like glycosylation. 相似文献
950.