全文获取类型
收费全文 | 2907篇 |
免费 | 234篇 |
国内免费 | 4篇 |
专业分类
3145篇 |
出版年
2023年 | 20篇 |
2022年 | 43篇 |
2021年 | 104篇 |
2020年 | 52篇 |
2019年 | 66篇 |
2018年 | 77篇 |
2017年 | 56篇 |
2016年 | 93篇 |
2015年 | 175篇 |
2014年 | 196篇 |
2013年 | 227篇 |
2012年 | 223篇 |
2011年 | 229篇 |
2010年 | 150篇 |
2009年 | 117篇 |
2008年 | 171篇 |
2007年 | 164篇 |
2006年 | 142篇 |
2005年 | 136篇 |
2004年 | 134篇 |
2003年 | 121篇 |
2002年 | 83篇 |
2001年 | 23篇 |
2000年 | 17篇 |
1999年 | 17篇 |
1998年 | 27篇 |
1997年 | 18篇 |
1996年 | 9篇 |
1995年 | 19篇 |
1994年 | 21篇 |
1993年 | 24篇 |
1992年 | 12篇 |
1991年 | 17篇 |
1990年 | 12篇 |
1989年 | 10篇 |
1988年 | 5篇 |
1987年 | 9篇 |
1985年 | 13篇 |
1984年 | 9篇 |
1983年 | 10篇 |
1982年 | 12篇 |
1981年 | 9篇 |
1980年 | 8篇 |
1979年 | 8篇 |
1978年 | 8篇 |
1977年 | 11篇 |
1976年 | 9篇 |
1975年 | 7篇 |
1974年 | 5篇 |
1973年 | 6篇 |
排序方式: 共有3145条查询结果,搜索用时 0 毫秒
91.
Danielle Rodrigues Garcia Felipe Rodrigues de Souza Ana Paula Guimarães Teodorico Castro Ramalho Alcino Palermo de Aguiar 《Journal of biomolecular structure & dynamics》2013,31(17):4569-4579
AbstractAcknowledging the importance of studies toward the development of measures against terrorism and bioterrorism, this study aims to contribute to the design of new prototypes of potential drugs against smallpox. Based on a former study, nine synthetic feasible prototypes of selective inhibitors for thymidylate kinase from Variola virus (VarTMPK) were designed and submitted to molecular docking, molecular dynamics simulations and binding energy calculations. The compounds are simplifications of two more complex scaffolds, with a guanine connected to an amide or alcohol through a spacer containing ether and/or amide groups, formerly suggested as promising for the design of selective inhibitors of VarTMPK. Our study showed that, despite the structural simplifications, the compounds presented effective energy values in interactions with VarTMPK and HssTMPK and that the guanine could be replaced by a simpler imidazole ring linked to a –NH2 group, without compromising the affinity for VarTMPK. It was also observed that a positive charge in the imidazole ring is important for the selectivity toward VarTMPK and that an amide group in the spacer does not contribute to selectivity. Finally, prototype 3 was pointed as the most promising to be synthesized and experimentally evaluated.Communicated by Ramaswamy H. Sarma 相似文献
92.
Alexander S. Fridman Viktor Brabec Samvel G. Haroutiunian Roger M. Wartell Dmitri Y. Lando 《Journal of biomolecular structure & dynamics》2013,31(4):533-545
Abstract DNA interstrand cross-links are usually formed due to bidentate covalent or coordination binding of a cross-linking agent to nucleotides of different strands. However interstrand linkages can be also caused by any type of chemical modification that gives rise to a strong local stabilization of the double helix. These stabilized sites conserve their helical structure and prevent local and total strand separation at temperatures above the melting of ordinary AT and GC base pairs. This local stabilization makes DNA melting fully reversible and independent of strand concentration like ordinary covalent interstrand cross-links. The stabilization can be caused by all the types of chemical modifications (interstrand cross-links, intrastrand cross-links or monofunctional adducts) if they give rise to a strong enough local stabilization of the double helix. Our calculation demonstrates that an increase in stability by 25 to 30 kcal in the free energy of a single base pair of the double helix is sufficient for this “cross-linking effect” (i.e. conserving the helicity of this base pair and preventing strand separation after melting of ordinary base pairs). For the situation where there is more then one stabilized site in a DNA duplex (e.g., 1 stabilized site per 1000 bp), a lower stabilization per site is sufficient for the “cross-linking effect” (18–20 kcal). A substantial increase in DNA stability was found in various experimental studies for some metal-based anti-tumor compounds. These compounds may give rise to the effect described above. If ligand induced stabilization is distributed among several neighboring base pairs, a much lower minimum increase per stabilized base pair is sufficient to produce the cross-linking effect (1 bp- 24.4 kcal; 5 bp- 5.3 kcal; 10 bp- 2.9 kcal, 25 bp- 1.4 kcal; 50 bp- 1.0 kcal). The relatively weak non-covalent binding of histones or protamines that cover long regions of DNA (20–40 bp) can also cause this effect if the salt concentration of the solution is sufficiently low to cause strong local stabilization of the double helix. Stretches of GC pairs more than 25 bp in length inserted into poly(AT) DNA also exhibit properties of stabilizing interstrand cross-links. 相似文献
93.
Various treatments have been proposed to attenuate and eventually inhibit the generation of acid mine drainage (AMD) or acid-rock drainage (ARD). The addition of Natural Phosphate Rocks (NPR) to mining wastes has been shown to reduce acid generation. The biogeochemical reactions underlying the phosphate precipitation reactions are however poorly understood, even though the chemical reactions are well defined. The present study was designed to study the role of solution chemistry and bacterial activity on phosphate precipitation on waste rock surfaces. Waste rock samples (rich in sulphides) previously weathered for 989 days in the presence of NPR were submersed in 2 different phosphate-rich growth media in order to enhance the growth of acidophilic and neutrophilic bacteria. DAPI and FISH analyses revealed that most cells belonged to the bacteria domain, and that alpha- and beta-proteobacteria were the dominant neutrophiles. ESEM, SEM and TEM observations of the samples revealed the presence of a biofilm on the surface of the rocks at both pH conditions. Bacteria and fine-grained precipitates were trapped in an exopolymer matrix. At low pH, the formation of fine precipitates rich in Fe and P within the biofilm corresponded to a decline of phosphate concentrations in the growth medium. This was in agreement with the solubility calculations which indicated that the medium became over-saturated with respect to some Fe-phosphate minerals. In the pH neutral system, solubility calculations indicated that Ca- and Mg-phosphate minerals were stable, but they were not detected in the biofilm. Solubility calculations also indicated that vivianite became unstable over time, which could explain the release of soluble phosphate over time in the pH neutral system. Our results showed that precipitation reactions played an important role in the solubility of phosphate in both systems, but a series of complex nucleation reactions involving bacterial exopolymers and the presence of microenvironments within the biofilms were likely important factors as well. Our findings also imply that the reduction of acid generation in NPR-treated waste rocks could be due in part to the formation of biofilms on the rock surfaces because the biofilms would act as a physical and chemcial barrier to limit the extent of pyrite oxidation. 相似文献
94.
Sulfate-reducing bacteria (SRB) are thought to be actively involved in the cycling of sulfur in acidic mine tailings. However, most studies have used circumstantial evidence to assess microbial sulfate activity in such environments. In order to fully ascertain the role of sulfate-reducing bacteria (SRB) in sulfur cycling in acidic mine tailings, we measured sulfate reduction rates, sulfur isotopic composition of reduced sulfide fractions, porewaters and solid-phase geochemistry and SRB populations in four different Cu-Zn tailings located in Timmins, Ontario, Canada. The tailings were sampled in the summer and in the spring, shortly after snowmelt. The results first indicate that all four sites showed very high sulfate reduction rates in the summer (~100–1000 nmol cm? 3d?1), which corresponded to the presence of sulfide in the porewaters and to high SRB populations. In some of the sites, zones of microbial sulfate reduction also corresponded to a decline of organic carbon and to an apparent pyrite (with slightly negative δ34S values) enrichment around the same depth. Microbial sulfate reduction was also important in permanently acidic (pH 2–3) mine tailings sites, suggesting that SRB can be active under very acidic conditions. Secondly, the results showed that microbial sulfate reduction was greatly reduced in the spring, suggesting that temperature might be a key factor in the activity of SRB. However, a closer look at the results indicated that temperature was not the sole factor and that acidic conditions and limited substrate availability in the spring appeared to be important as well in limiting microbial sulfate par reduction in sulfidic mine tailings. Finally, the results indicate that sulfur undergoes rapid cycling throughout the year and that microbial sulfate reduction and metal sulfide precipitation do not appear to be a permanent sink for metals. 相似文献
95.
Sanya Fanous Danielle H. Guez‐Barber Evan M. Goldart Regina Schrama Florence R. M. Theberge Yavin Shaham Bruce T. Hope 《Journal of neurochemistry》2013,124(1):100-108
Cue‐induced heroin seeking after prolonged withdrawal is associated with neuronal activation and altered gene expression in prefrontal cortex (PFC). However, these previous studies assessed gene expression in all neurons regardless of their activity state during heroin seeking. Using Fos as a marker of neural activity, we describe distinct molecular alterations induced in activated versus non‐activated neurons during cue‐induced heroin seeking after prolonged withdrawal. We trained rats to self‐administer heroin for 10 days (6 h/day) and assessed cue‐induced heroin seeking in extinction tests after 14 or 30 days. We used fluorescent‐activated cell sorting (FACS) to purify Fos‐positive and Fos‐negative neurons from PFC 90 min after extinction testing. Flow cytometry showed that Fos‐immunoreactivity was increased in less than 10% of sparsely distributed PFC neurons. mRNA levels of the immediate early genes fosB, arc, egr1, and egr2, as well as npy and map2k6, were increased in Fos‐positive, but not Fos‐negative, neurons. In support of these findings, double‐label immunohistochemistry indicated substantial coexpression of neuropeptide Y (NPY)‐ and Arc‐immunoreactivity in Fos‐positive neurons. Our data indicate that cue‐induced relapse to heroin seeking after prolonged withdrawal induces unique molecular alterations within activated PFC neurons that are distinct from those observed in the surrounding majority of non‐activated neurons. 相似文献
96.
97.
Danielle S. Kurin 《American journal of physical anthropology》2013,152(4):484-494
This study evaluates trepanations from five well‐contextualized prehistoric sites in the south‐central highlands of Andahuaylas, Peru. The emergence of trepanation in this region coincides with the collapse of the Wari Empire, ca. ad 1000. Thirty‐two individuals from Andahuaylas, AMS radiocarbon dated to the early Late Intermediate Period (ca. ad 1000–1250), were found to have 45 total trepanations. Various surgical techniques were being employed concurrently throughout the region. Scraping trepanations evinced the highest survival rate; circular grooving, drilling and boring, and linear cutting were far less successful. Evidence of perioperative procedures like hair shaving, poultice application, and possible cranioplasty use aimed to ensure the survival of a trepanation recipient. Postmortem trepanations, also present in Andahuaylas, were likely executed on corpses as a means of better understanding cranial anatomy and improving techniques. Similarities in trepanation patterns throughout the region attest to common motivations to engage in surgery. Although moderate physical head trauma seems to be the impetus for intervention in many cases of trepanation, other motivations included physiological and possibly psychosomatic factors. Nevertheless, treatment was not for everyone. In Andahuaylas, trepanations were withheld from subadults, females, and those individuals who practiced cranial modification. Am J Phys Anthropol 152:484–494, 2013. © 2013 Wiley Periodicals, Inc. 相似文献
98.
Scott J. Gratz Alexander M. Cummings Jennifer N. Nguyen Danielle C. Hamm Laura K. Donohue Melissa M. Harrison Jill Wildonger Kate M. O’Connor-Giles 《Genetics》2013,194(4):1029-1035
We have adapted a bacterial CRISPR RNA/Cas9 system to precisely engineer the Drosophila genome and report that Cas9-mediated genomic modifications are efficiently transmitted through the germline. This RNA-guided Cas9 system can be rapidly programmed to generate targeted alleles for probing gene function in Drosophila. 相似文献
99.
Après avoir revu l'ensemble des caractères morphologiques, anatomiques, caryologiques, embryologiques, phytochimiques, sérologiques et palynologiques les auteurs concluent à la nécessité de séparer les deux genres Cneorum et Neochamaelea et de rattacher la famille aux Rutales. Par l'étude détaillée des caractères du pollen, ils montrent également que l'ultrastructure de l'exine est identique dans les deux genres, bien que l'ornementation et le nombre des apertures soient différents. Le type pollinique des Cneoraceae est comparable à celui des Rutaceae, Simaroubaceae et vient étayer l'opinion fréquemment admise que la famille appartient à l'ordre des Rutales. 相似文献
100.
Yanqin Liu Tara L. Pukala Ian F. Musgrave Danielle M. Williams Francis C. Dehle John A. Carver 《Bioorganic & medicinal chemistry letters》2013,23(23):6336-6340
Many protein misfolding diseases, for example, Alzheimer’s, Parkinson’s and Huntington’s, are characterised by the accumulation of protein aggregates in an amyloid fibrillar form. Natural products which inhibit fibril formation are a promising avenue to explore as therapeutics for the treatment of these diseases. In this study we have shown, using in vitro thioflavin T assays and transmission electron microscopy, that grape seed extract inhibits fibril formation of kappa-casein (κ-CN), a milk protein which forms amyloid fibrils spontaneously under physiological conditions. Among the components of grape seed extract, gallic acid was the most active component at inhibiting κ-CN fibril formation, by stabilizing κ-CN to prevent its aggregation. Concomitantly, gallic acid significantly reduced the toxicity of κ-CN to pheochromocytoma12 cells. Furthermore, gallic acid effectively inhibited fibril formation by the amyloid-beta peptide, the putative causative agent in Alzheimer’s disease. It is concluded that the gallate moiety has the fibril-inhibitory activity. 相似文献