全文获取类型
收费全文 | 1569篇 |
免费 | 67篇 |
国内免费 | 11篇 |
专业分类
化学 | 1100篇 |
晶体学 | 7篇 |
力学 | 51篇 |
数学 | 274篇 |
物理学 | 215篇 |
出版年
2023年 | 13篇 |
2022年 | 29篇 |
2021年 | 29篇 |
2020年 | 21篇 |
2019年 | 32篇 |
2018年 | 23篇 |
2017年 | 16篇 |
2016年 | 40篇 |
2015年 | 54篇 |
2014年 | 59篇 |
2013年 | 72篇 |
2012年 | 96篇 |
2011年 | 118篇 |
2010年 | 57篇 |
2009年 | 63篇 |
2008年 | 98篇 |
2007年 | 102篇 |
2006年 | 101篇 |
2005年 | 73篇 |
2004年 | 80篇 |
2003年 | 68篇 |
2002年 | 60篇 |
2001年 | 18篇 |
2000年 | 23篇 |
1999年 | 24篇 |
1998年 | 13篇 |
1997年 | 15篇 |
1996年 | 19篇 |
1995年 | 15篇 |
1994年 | 15篇 |
1993年 | 9篇 |
1992年 | 11篇 |
1991年 | 10篇 |
1990年 | 14篇 |
1988年 | 9篇 |
1987年 | 9篇 |
1986年 | 8篇 |
1985年 | 9篇 |
1984年 | 7篇 |
1983年 | 7篇 |
1982年 | 12篇 |
1981年 | 10篇 |
1980年 | 10篇 |
1979年 | 10篇 |
1978年 | 9篇 |
1977年 | 5篇 |
1976年 | 6篇 |
1975年 | 6篇 |
1974年 | 7篇 |
1915年 | 4篇 |
排序方式: 共有1647条查询结果,搜索用时 0 毫秒
81.
Johannes Karges Uttara Basu Olivier Blacque Hui Chao Gilles Gasser 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2019,131(40):14472-14478
The use of photodynamic therapy (PDT) to treat cancer has received increasing attention over the last years. However, the clinically used photosensitisers (PSs) have some limitations that include poor aqueous solubility, hepatotoxicity, photobleaching, aggregation, and slow clearance from the body, so the design of new classes of PSs is of great interest. We present the use of bis(dipyrrinato)zinc(II) complexes with exceptionally long lifetimes as efficient PDT PSs. Based on the heavy‐atom effect, intersystem crossing of these complexes changes the excited state from singlet to a triplet state, thereby enabling singlet oxygen generation. To overcome the limitation of quenching effects in water and improve water solubility, the lead compound 3 was encapsulated in a polymer matrix. It showed impressive phototoxicity upon irradiation at 500 nm in various monolayer cancer cells as well as 3D multicellular tumour spheroids, without observed dark toxicity. 相似文献
82.
Loïc Quinton Denis Servent Emmanuelle Girard Jordi Molgó Jean-Pierre Le Caer Christian Malosse El Ali Haidar Alain Lecoq Nicolas Gilles Julia Chamot-Rooke 《Analytical and bioanalytical chemistry》2013,405(15):5341-5351
Nicotinic acetylcholine receptors (nAChRs) are one of the most important families in the ligand-gated ion channel superfamily due to their involvement in primordial brain functions and in several neurodegenerative pathologies. The discovery of new ligands which can bind with high affinity and selectivity to nAChR subtypes is of prime interest in order to study these receptors and to potentially discover new drugs for treating various pathologies. Predatory cone snails of the genus Conus hunt their prey using venoms containing a large number of small, highly structured peptides called conotoxins. Conotoxins are classified in different structural families and target a large panel of receptors and ion channels. Interestingly, nAChRs represent the only subgroup for which Conus has developed seven distinct families of conotoxins. Conus venoms have thus received much attention as they could represent a potential source of selective ligands of nAChR subtypes. We describe the mass spectrometric-based approaches which led to the discovery of a novel α-conotoxin targeting muscular nAChR from the venom of Conus ermineus. The presence of several posttranslational modifications complicated the N-terminal sequencing. To discriminate between the different possible sequences, analogs with variable N-terminus were synthesized and fragmented by MS/MS. Understanding the fragmentation pathways in the low m/z range appeared crucial to determine the right sequence. The biological activity of this novel α-conotoxin (α-EIIA) that belongs to the unusual α4/4 subfamily was determined by binding experiments. The results revealed not only its selectivity for the muscular nAChR, but also a clear discrimination between the two binding sites described for this receptor. 相似文献
83.
van der Rest G Hui R Frison G Chamot-Rooke J 《Journal of the American Society for Mass Spectrometry》2011,22(9):1631-1644
Electron capture dissociation (ECD) of a series of five residue peptides led to the observation that these small peptides
did not lead to the formation of the usual c/z ECD fragments, but to a, b, y, and w fragments. In order to determine how general this behavior is for small sized peptides, the effect of peptide size on ECD
fragments using a complete set of ECD spectra from the SwedECD spectra database was examined. Analysis of the database shows
that b and w fragments are favored for small peptide sizes and that average fragment size shows a linear relationship to parent peptide
size for most fragment types. From these data, it appears that most of the w fragments are not secondary fragments of the major z ions, in sharp contrast with the proposed mechanism leading to these ions. These data also show that c fragment distributions depend strongly on the nature of C-terminal residue basic site: arginine leads to loss of short neutral
fragments, whereas lysine leads to loss of longer neutral fragments. It also appears that b ions might be produced by two different mechanisms depending on the parent peptide size. A model for the fragmentation pathways
in competition is proposed. These relationships between average fragment size and parent peptide size could be further exploited
also for CID fragment spectra and could be included in fragmentation prediction algorithms. 相似文献
84.
Armand Gellis Charline Kieffer Nicolas Primas Gilles Lanzada Michel Giorgi Pierre Verhaeghe Patrice Vanelle 《Tetrahedron》2014
We report herein a new methodology for synthesizing quinazoline derivatives bearing a heteroarylamino moiety at position-4 of the quinazoline ring. As an alternative to the Buchwald–Hartwig cross-coupling reaction, which appears, until now, as the only efficient way to react 4-chloroquinazolines with numerous amino nitrogen-containing heterocycles displaying poor nucleophilicity, we developed a DMAP-catalyzed reaction involving microwave irradiation. Optimization of the reaction conditions led to the use of 30 mol % of DMAP in toluene, using a monomode microwave reactor and sealed vials. Moreover, the SNAr reaction intermediate salt was isolated and fully characterized. Finally, the procedure was extended to two different 2-substituted-quinazoline series and also to various anilines, demonstrating that this approach was a general efficient way to access to such 4-substituted quinazoline scaffolds of high pharmaceutical interest. 相似文献
85.
Desulfurized gypsum (DG) as a soil modifier imparts it with bulk solid sulfite. The Fe(III)–sulfite process in the liquid phase has shown great potential for the rapid removal of As(III), but the performance and mechanism of this process using DG as a sulfite source in aqueous solution remains unclear. In this work, employing solid CaSO3 as a source of SO32−, we have studied the effects of different conditions (e.g., pH, Fe dosage, sulfite dosage) on As(III) oxidation in the Fe(III)–CaSO3 system. The results show that 72.1% of As(III) was removed from solution by centrifugal treatment for 60 min at near-neutral pH. Quenching experiments have indicated that oxidation efficiencies of As(III) are due at 67.5% to HO•, 17.5% to SO5•− and 15% to SO4•−. This finding may have promising implications in developing a new cost-effective technology for the treatment of arsenic-containing water using DG. 相似文献
86.
87.
The binding of a set of 10 triphenoxypyridine derivatives to two serine proteases, factor Xa and trypsin, has been used to analyze factors related to sampling and convergence in free energy calculations based on molecular dynamics simulation techniques. The inhibitors investigated were initially proposed as part of the Critical Assessment of Techniques for Free Energy Evaluation (CATFEE) project for which no experimental results nor any assessment of the predictions submitted by various groups have ever been published. The inhibitors studied represent a severe challenge for explicit free energy calculations. The mutations from one compound to another involve up to 19 atoms, the creation and annihilation of net charge and several alternate binding modes. Nevertheless, we demonstrate that it is possible to obtain highly converged results (+/- 5-10 kJ/mol) even for such complex multi-atom mutations by simulating on a nanosecond time scale. This is achieved by using soft-core potentials to facilitate the creation and deletion of atoms and by a careful choice of mutation pathway. The results show that given modest computational resources, explicit free energy calculations can be successfully applied to realistic problems in drug design. 相似文献
88.
Hideki Moriishi Osamu Kikuchi Keizo Suzuki Gilles Klopman 《Theoretical chemistry accounts》1984,64(5):319-338
Reaction potential maps (RPM) have been introduced as a new tool for the study of molecular reactivity. The equipotential energy maps, which are created on given planes around a molecule, define reaction contours towards specific counter-reagent models and are evaluated by perturbation theory. Since the calculated interaction energy involves electrostatic, polarization, exchange, and charge transfer energies, the RPM's can be used to predict site selectivity in a variety of chemical reactions. We found that the calculated RPM's of the SCN– anion explained well the experimental observations that it reacts at the S atom with soft electrophiles and at the N atom with hard electrophiles. The difference in reactivity between SCN– and OCN– was clearly shown by the RPM's of these anions. The ambident nucleophilic nature of the NO
2
–
and the CH2CHO– anions was also well represented by their RPM's. 相似文献
89.
Trouche N Wieckowski S Sun W Chaloin O Hoebeke J Fournel S Guichard G 《Journal of the American Chemical Society》2007,129(44):13480-13492
Synthetic multivalent ligands, owing to the presence of multiple copies of a recognition motif attached to a central scaffold, can mediate clustering of cell surface receptors and thereby function as effector molecules. This paper dissects the relationship between structure and effector function of synthetic multivalent ligands targeting CD40, a cell surface receptor of the tumor necrosis factor receptor (TNF-R) superfamily. Triggering CD40 signaling in vivo can be used to enhance immunity against intracellular pathogens or tumors. A series of multimeric molecules has been prepared by systematically varying the shape and the valency of the central scaffold, the nature and the length of the linker as well as the sequence of the receptor binding motif. The data reported here (i) suggest that radial distribution of CD40-binding units and C3-symmetry are preferred for optimal binding to CD40 and signaling, (ii) underscore the importance of choosing an appropriate linker to connect the receptor binding motif to the central scaffold, and (iii) show the versatility of planar cyclic alpha- and beta-peptides as templates for the design of CD40L mimetics. In particular, the (Ahx)3-B trimeric scaffold-linker combination equally accommodated binding elements derived from distinct CD40L hot-spot regions including AA" loop and beta-strand E. The use of miniCD40Ls such as those reported here is complementary to other approaches (recombinant ligands, agonistic anti-receptor antibodies) and may find interesting therapeutic applications. Furthermore, the results disclosed in this paper provide the basis for future design of other TNF family member mimetics. 相似文献
90.