全文获取类型
收费全文 | 1950篇 |
免费 | 134篇 |
国内免费 | 4篇 |
专业分类
2088篇 |
出版年
2023年 | 17篇 |
2022年 | 40篇 |
2021年 | 44篇 |
2020年 | 22篇 |
2019年 | 35篇 |
2018年 | 57篇 |
2017年 | 38篇 |
2016年 | 52篇 |
2015年 | 76篇 |
2014年 | 108篇 |
2013年 | 138篇 |
2012年 | 169篇 |
2011年 | 161篇 |
2010年 | 108篇 |
2009年 | 87篇 |
2008年 | 121篇 |
2007年 | 140篇 |
2006年 | 104篇 |
2005年 | 124篇 |
2004年 | 105篇 |
2003年 | 92篇 |
2002年 | 90篇 |
2001年 | 11篇 |
2000年 | 7篇 |
1999年 | 16篇 |
1998年 | 20篇 |
1997年 | 18篇 |
1996年 | 17篇 |
1995年 | 11篇 |
1994年 | 11篇 |
1993年 | 6篇 |
1992年 | 8篇 |
1991年 | 1篇 |
1990年 | 3篇 |
1989年 | 2篇 |
1988年 | 1篇 |
1987年 | 1篇 |
1986年 | 1篇 |
1985年 | 1篇 |
1984年 | 3篇 |
1983年 | 1篇 |
1982年 | 4篇 |
1981年 | 4篇 |
1980年 | 3篇 |
1979年 | 1篇 |
1978年 | 4篇 |
1976年 | 2篇 |
1969年 | 2篇 |
1968年 | 1篇 |
排序方式: 共有2088条查询结果,搜索用时 0 毫秒
21.
Zeifman AA Stroylov VS Novikov FN Stroganov OV Zakharenko AL Khodyreva SN Lavrik OI Chilov GG 《Journal of molecular modeling》2012,18(6):2553-2566
Virtual fragment screening could be a promising alternative to existing experimental screening techniques. However, reliable methods of in silico fragment screening are yet to be established and validated. In order to develop such an approach we first checked how successful the existing molecular docking methods can be in predicting fragment binding affinities and poses. Using our Lead Finder docking software the RMSD of the binding energy prediction was observed to be 1.35 kcal/mol(-1) on a set of 26 experimentally characterized fragment inhibitors, and the RMSD of the predicted binding pose from the experimental one was <1.5 ?. Then, we explored docking of 68 fragments obtained from 39 drug molecules for which co-crystal structures were available from the PDB. It appeared that fragments that participate in oriented non-covalent interactions, such as hydrogen bonds and metal coordination, could be correctly docked in 70-80% of cases suggesting the potential success of rediscovering of corresponding drugs by in silico fragment approach. Based on these findings we've developed a virtual fragment screening technique which involved structural filtration of protein-ligand complexes for specific interactions and subsequent clustering in order to minimize the number of preferable starting fragment candidates. Application of this method led to 2 millimolar-scale fragment PARP1 inhibitors with a new scaffold. 相似文献
22.
Buzdin A Ustyugova S Khodosevich K Mamedov I Lebedev Y Hunsmann G Sverdlov E 《Genomics》2003,81(2):149-156
Using 40 known human-specific LTR sequences, we have derived a consensus sequence for an evolutionary young HERV-K (HML-2) LTR family, which was named the HS family. In the human genome the HS family is represented by approximately 150-160 LTR sequences, 90% of them being human-specific (hs). The family can be subdivided into two subfamilies differing in five linked nucleotide substitutions: HS-a and HS-b of 5.8 and 10.3 Myr evolutionary ages, respectively. The HS-b subfamily members were transpositionally active both before the divergence of the human and chimpanzee ancestor lineages and after it in both lineages. The HS-a subfamily comprises only hs LTRs. These and other data strongly suggest that at least three "master genes" of HERV-K (HML-2) LTRs were active in the human ancestor lineage after the human-chimpanzee divergence. We also found hs HERV-K (HML-2) LTRs integrations in introns of 12 human genes and identified 13 new hs HERV-K (HML-2) LTRs. 相似文献
23.
Eli K. Moore Laura Villanueva Ellen C. Hopmans W. Irene C. Rijpstra Anchelique Mets Svetlana N. Dedysh Jaap S. Sinninghe Damsté 《Applied and environmental microbiology》2015,81(18):6333-6344
Northern wetlands make up a substantial terrestrial carbon sink and are often dominated by decay-resistant Sphagnum mosses. Recent studies have shown that planctomycetes appear to be involved in degradation of Sphagnum-derived debris. Novel trimethylornithine (TMO) lipids have recently been characterized as abundant lipids in various Sphagnum wetland planctomycete isolates, but their occurrence in the environment has not yet been confirmed. We applied a combined intact polar lipid (IPL) and molecular analysis of peat cores collected from two northern wetlands (Saxnäs Mosse [Sweden] and Obukhovskoye [Russia]) in order to investigate the preferred niche and abundance of TMO-producing planctomycetes. TMOs were present throughout the profiles of Sphagnum bogs, but their concentration peaked at the oxic/anoxic interface, which coincided with a maximum abundance of planctomycete-specific 16S rRNA gene sequences. The sequences detected at the oxic/anoxic interface were affiliated with the Isosphaera group, while sequences present in the anoxic peat layers were related to an uncultured planctomycete group. Pyrosequencing-based analysis identified Planctomycetes as the major bacterial group at the oxic/anoxic interface at the Obukhovskoye peat (54% of total 16S rRNA gene sequence reads), followed by Acidobacteria (19% reads), while in the Saxnäs Mosse peat, Acidobacteria were dominant (46%), and Planctomycetes contributed to 6% of the total reads. The detection of abundant TMO lipids in planctomycetes isolated from peat bogs and the lack of TMO production by cultures of acidobacteria suggest that planctomycetes are the producers of TMOs in peat bogs. The higher accumulation of TMOs at the oxic/anoxic interface and the change in the planctomycete community with depth suggest that these IPLs could be synthesized as a response to changing redox conditions at the oxic/anoxic interface. 相似文献
24.
25.
26.
Unloading of homologous recombination factors is required for restoring double‐stranded DNA at damage repair loci 下载免费PDF全文
Yulia Vasianovich Veronika Altmannova Oleksii Kotenko Matthew D Newton Lumir Krejci Svetlana Makovets 《The EMBO journal》2017,36(2):213-231
Cells use homology‐dependent DNA repair to mend chromosome breaks and restore broken replication forks, thereby ensuring genome stability and cell survival. DNA break repair via homology‐based mechanisms involves nuclease‐dependent DNA end resection, which generates long tracts of single‐stranded DNA required for checkpoint activation and loading of homologous recombination proteins Rad52/51/55/57. While recruitment of the homologous recombination machinery is well characterized, it is not known how its presence at repair loci is coordinated with downstream re‐synthesis of resected DNA. We show that Rad51 inhibits recruitment of proliferating cell nuclear antigen (PCNA), the platform for assembly of the DNA replication machinery, and that unloading of Rad51 by Srs2 helicase is required for efficient PCNA loading and restoration of resected DNA. As a result, srs2Δ mutants are deficient in DNA repair correlating with extensive DNA processing, but this defect in srs2Δ mutants can be suppressed by inactivation of the resection nuclease Exo1. We propose a model in which during re‐synthesis of resected DNA, the replication machinery must catch up with the preceding processing nucleases, in order to close the single‐stranded gap and terminate further resection. 相似文献
27.
Immunotherapy with Bacillus Calmette–Guérin (BCG)—an attenuated strain of Mycobacterium bovis (M. bovis) used for anti tuberculosis immunization—is a clinically established procedure for the treatment of superficial bladder cancer.
However, the mode of action has not yet been fully elucidated, despite much extensive biological experience. The purpose of
this paper is to develop a first mathematical model that describes tumor-immune interactions in the bladder as a result of
BCG therapy. A mathematical analysis of the ODE model identifies multiple equilibrium points, their stability properties,
and bifurcation points. Intriguing regimes of bistability are identified in which treatment has potential to result in a tumor-free
equilibrium or a full-blown tumor depending only on initial conditions. Attention is given to estimating parameters and validating
the model using published data taken from in vitro, mouse and human studies. The model makes clear that intensity of immunotherapy
must be kept in limited bounds. While small treatment levels may fail to clear the tumor, a treatment that is too large can
lead to an over-stimulated immune system having dangerous side effects for the patient. 相似文献
28.
After the liver, the pancreas contains the second highest level of folate among human tissues, and folate deficiency adversely affects its physiological function. Despite that, nothing is currently known about the cellular mechanisms involved in folate uptake by cells of this important exocrine organ or about folate uptake regulation. We have begun to address these issues, and in this report we present the results of our findings on the mechanism of folate uptake by the human-derived pancreatic MIA PaCa-2 cells. Our results show folic acid uptake to be 1) temperature and energy dependent; 2) pH dependent, with a markedly higher uptake at acidic pH compared with neutral or alkaline pH; 3) Na+ independent; 4) saturable as a function of substrate concentration (apparent Km = 0.762 ± 0.10 µM); 5) inhibited (with similar affinity) by reduced, substituted, and oxidized folate derivatives; and 6) sensitive to the inhibitory effect of anion transport inhibitors. RT-PCR and Western blot analysis showed expression of the human reduced folate carrier (hRFC) at the RNA and protein levels, respectively. The functional contribution of hRFC in carrier-mediated folate uptake was confirmed by gene silencing using gene-specific small interfering RNA. Evidence also was found suggesting that the folate uptake process by MIA PaCa-2 cells is regulated by cAMP- and protein tyrosine kinase (PTK)-mediated pathways. These studies demonstrate for the first time the involvement of a specialized, acidic pH-dependent, carrier-mediated mechanism for folate uptake by human pancreatic MIA PaCa-2 cells. The results also show the involvement of hRFC in the uptake process and suggest the possible involvement of intracellular cAMP- and PTK-mediated pathways in the regulation of folate uptake. human reduced folate carrier; small interfering RNA; transport regulation 相似文献
29.
V. Carolina Figueroa Helland Svetlana Postnova Udo Schwarz Jürgen Kurths Bernd Kundermann Ulrich Hemmeter Hans A. Braun 《Journal of biological physics》2008,34(3-4):393-404
In healthy subjects, sleep has a typical structure of three to five cyclic transitions between different sleep states. In major depression, this regular pattern is often destroyed but can be reestablished during successful treatment. The differences between healthy and abnormal sleep are generally assessed in a time-consuming process, which consists of determining the nightly variations of the sleep states (the hypnogram) based on visual inspection of the electroencephalogram (EEG), electrooculogram, and electromyogram. In this study, three different methods of sleep EEG analysis (spectrum, outlier, and recurrence analysis) have been examined with regard to their ability to extract information about treatment effects in patients with major depression. Our data suggest that improved sleep patterns during treatment with antidepressant medication can be identified with an appropriate analysis of the EEG. By comparing different methods, we have found that many treatment effects identified by spectrum analysis can be reproduced by the much simpler technique of outlier analysis. Finally, the cyclic structure of sleep and its modification by antidepressant treatment is best illustrated by a non-linear approach, the so-called recurrence method. 相似文献