全文获取类型
收费全文 | 6310篇 |
免费 | 813篇 |
国内免费 | 496篇 |
专业分类
化学 | 6348篇 |
晶体学 | 36篇 |
力学 | 55篇 |
综合类 | 175篇 |
数学 | 115篇 |
物理学 | 890篇 |
出版年
2024年 | 8篇 |
2023年 | 88篇 |
2022年 | 371篇 |
2021年 | 438篇 |
2020年 | 392篇 |
2019年 | 252篇 |
2018年 | 209篇 |
2017年 | 214篇 |
2016年 | 333篇 |
2015年 | 329篇 |
2014年 | 353篇 |
2013年 | 465篇 |
2012年 | 442篇 |
2011年 | 365篇 |
2010年 | 342篇 |
2009年 | 394篇 |
2008年 | 338篇 |
2007年 | 316篇 |
2006年 | 301篇 |
2005年 | 296篇 |
2004年 | 256篇 |
2003年 | 199篇 |
2002年 | 134篇 |
2001年 | 100篇 |
2000年 | 108篇 |
1999年 | 115篇 |
1998年 | 86篇 |
1997年 | 76篇 |
1996年 | 42篇 |
1995年 | 43篇 |
1994年 | 46篇 |
1993年 | 32篇 |
1992年 | 26篇 |
1991年 | 20篇 |
1990年 | 11篇 |
1989年 | 13篇 |
1988年 | 14篇 |
1987年 | 5篇 |
1986年 | 14篇 |
1985年 | 7篇 |
1984年 | 9篇 |
1983年 | 5篇 |
1982年 | 5篇 |
1981年 | 2篇 |
1979年 | 1篇 |
1978年 | 1篇 |
1959年 | 3篇 |
排序方式: 共有7619条查询结果,搜索用时 265 毫秒
991.
Dr. Jun Ma Chao Ma Dr. Jingjing Li Dr. Yao Sun Prof. Fangfu Ye Prof. Kai Liu Prof. Hongjie Zhang 《Chemistry (Weinheim an der Bergstrasse, Germany)》2020,26(53):12101-12110
Alzheimer's disease (AD) is one of the most common neurodegenerative diseases and characterized by cognitive and memory impairments. Emerging evidence suggests that the extracellular matrix (ECM) in the brain plays an important role in the etiology of AD. It has been detected that the levels of ECM proteins have changed in the brains of AD patients and animal models. Some ECM components, for example, elastin and heparan sulfate proteoglycans, are considered to promote the upregulation of extracellular amyloid-beta (Aβ) proteins. In addition, collagen VI and laminin are shown to have interactions with Aβ peptides, which might lead to the clearance of those peptides. Thus, ECM proteins are involved in both amyloidosis and neuroprotection in the AD process. However, the molecular mechanism of neuronal ECM proteins on the pathophysiology of AD remains elusive. More investigation of ECM proteins with AD pathogenesis is needed, and this may lead to novel therapeutic strategies and biomarkers for AD. 相似文献
992.
Prof. Dr. Frank Heinrich Aria Salyapongse Akari Kumagai Dr. Fernando G. Dupuy Karpur Shukla Dr. Anja Penk Prof. Dr. Daniel Huster Prof. Dr. Robert K. Ernst Dr. Anna Pavlova Prof. Dr. James C. Gumbart Prof. Dr. Berthony Deslouches Prof. Dr. Y. Peter Di Prof. Dr. Stephanie Tristram-Nagle 《Chemistry (Weinheim an der Bergstrasse, Germany)》2020,26(28):6247-6256
In the quest for new antibiotics, two novel engineered cationic antimicrobial peptides (eCAPs) have been rationally designed. WLBU2 and D8 (all 8 valines are the d -enantiomer) efficiently kill both Gram-negative and -positive bacteria, but WLBU2 is toxic and D8 nontoxic to eukaryotic cells. We explore protein secondary structure, location of peptides in six lipid model membranes, changes in membrane structure and pore evidence. We suggest that protein secondary structure is not a critical determinant of bactericidal activity, but that membrane thinning and dual location of WLBU2 and D8 in the membrane headgroup and hydrocarbon region may be important. While neither peptide thins the Gram-negative lipopolysaccharide outer membrane model, both locate deep into its hydrocarbon region where they are primed for self-promoted uptake into the periplasm. The partially α-helical secondary structure of WLBU2 in a red blood cell (RBC) membrane model containing 50 % cholesterol, could play a role in destabilizing this RBC membrane model causing pore formation that is not observed with the D8 random coil, which correlates with RBC hemolysis caused by WLBU2 but not by D8. 相似文献
993.
Kanna Adachi Tomoshi Yamada Hayate Ishizuka Mana Oki Shunsuke Tsunogae Noriko Shimada Osamu Chiba Tatsuya Orihara Prof. Dr. Masafumi Hidaka Prof. Dr. Takatsugu Hirokawa Dr. Minami Odagi Prof. Dr. Keiichi Konoki Prof. Dr. Mari Yotsu-Yamashita Prof. Dr. Kazuo Nagasawa 《Chemistry (Weinheim an der Bergstrasse, Germany)》2020,26(9):2025-2033
A novel series of C12-keto-type saxitoxin (STX) derivatives bearing an unusual nonhydrated form of the ketone at C12 has been synthesized, and their NaV-inhibitory activity has been evaluated in a cell-based assay as well as whole-cell patch-clamp recording. Among these compounds, 11-benzylidene STX ( 3 a ) showed potent inhibitory activity against neuroblastoma Neuro 2A in both cell-based and electrophysiological analyses, with EC50 and IC50 values of 8.5 and 30.7 nm , respectively. Interestingly, the compound showed potent inhibitory activity against tetrodotoxin-resistant subtype of NaV1.5, with an IC50 value of 94.1 nm . Derivatives 3 a – d and 3 f showed low recovery rates from NaV1.2 subtype (ca 45–79 %) compared to natural dcSTX ( 2 ), strongly suggesting an irreversible mode of interaction. We propose an interaction model for the C12-keto derivatives with NaV in which the enone moiety in the STX derivatives 3 works as Michael acceptor for the carboxylate of Asp1717. 相似文献
994.
Pea protein isolate (PPI) and bean protein concentrate (BPC) were evaluated as fiber-forming vegetal source materials through electrospinning using various solvents. The effects of hexafluoroisopropanol (HFIP), trifluoroethanol (TFE), trifluoroacetic acid (TFA), formic acid (FA) and water on rheological and conformational properties of the protein solutions were determined. The morphology and molecular organization of the electrospun structures were studied. All PPI and BPC solutions displayed pseudoplastic behavior. Circular dichroism spectroscopy revealed that β-type turns and β-sheets were the dominant protein conformations in water, HFIP, and TFE. After electrospinning, most of the solutions afforded beads. Fiber-like morphologies were only obtained when BPC was dissolved in HFIP. BPC demonstrated better performance in the electrospinning process than PPI. Denaturation of the protein isolates was not sufficient to form fibers, the viscosity of the solution as well as the vapor pressure of the solvents played an important role in defining the morphology. 相似文献
995.
Adam I. Green Dr. Fruzsina Hobor Dr. Christopher P. Tinworth Dr. Stuart Warriner Prof. Andrew J. Wilson Prof. Adam Nelson 《Chemistry (Weinheim an der Bergstrasse, Germany)》2020,26(47):10682-10689
Protein–protein interactions (PPIs) provide a rich source of potential targets for drug discovery and biomedical science research. However, the identification of structural-diverse starting points for discovery of PPI inhibitors remains a significant challenge. Activity-directed synthesis (ADS), a function-driven discovery approach, was harnessed in the discovery of the p53/hDM2 PPI. Over two rounds of ADS, 346 microscale reactions were performed, with prioritisation on the basis of the activity of the resulting product mixtures. Four distinct and novel series of PPI inhibitors were discovered that, through biophysical characterisation, were shown to have promising ligand efficiencies. It was thus shown that ADS can facilitate ligand discovery for a target that does not have a defined small-molecule binding site, and can provide distinctive starting points for the discovery of PPI inhibitors. 相似文献
996.
Kentarou Sakamoto Dr. Misao Akishiba Takahiro Iwata Dr. Kazuya Murata Dr. Seiya Mizuno Dr. Kenichi Kawano Dr. Miki Imanishi Prof. Dr. Fumihiro Sugiyama Prof. Dr. Shiroh Futaki 《Angewandte Chemie (Weinheim an der Bergstrasse, Germany)》2020,132(45):20165-20173
Endocytic pathways are practical routes for the intracellular delivery of biomacromolecules. Along with this, effective strategies for endosomal cargo release into the cytosol are desired to achieve successful delivery. Focusing on compositional differences between the cell and endosomal membranes and the pH decrease within endosomes, we designed the lipid-sensitive and pH-responsive endosome-lytic peptide HAad. This peptide contains aminoadipic acid (Aad) residues, which serve as a safety catch for preferential permeabilization of endosomal membranes over cell membranes, and His-to-Ala substitutions enhance the endosomolytic activity. The ability of HAad to destabilize endosomal membranes was supported by model studies using large unilamellar vesicles (LUVs) and by increased intracellular delivery of biomacromolecules (including antibodies) into live cells. Cerebral ventricle injection of Cre recombinase with HAad led to Cre/loxP recombination in a mouse model, thus demonstrating potential applicability of HAad in vivo. 相似文献
997.
Kornelija Lasi Ana Bokuli Astrid Mili Biljana Nigovi Ana Mornar 《Biomedical chromatography : BMC》2019,33(8)
This paper presents lipophilicity and bio‐mimetic property determination of 15 phytoestrogens, namely biochanin A, daidzein, formononetin, genistein, genistein‐4,7‐dimethylether, prunetin, 3,4,7‐trihydroxyisoflavon, 4,6,7‐trihydroxyisoflavon, 4,6,7‐trimethoxyisoflavon, daidzin, genistin, ononin, sissotrin, coumestrol and coumestrol dimethylether. High‐performance liquid chromatography with fast gradient elution and Caco‐2 cell line were used to determine the physicochemical properties of selected phytoestrogens. Lipophilicity was determined on octadecyl‐sylane stationary phase using pH 2.0 and pH 7.4 buffers. Immobilized artificial membrane chromatography was used for prediction of interaction with biological membranes. Protein binding was measured on human serum albumin and α‐1‐acid‐glycoprotein (AGP) stationary phases. Caco‐2 assay was used as a gold standard for assessing in vitro permeability. The obtained results differentiate phytoestrogens according to their structure where aglycones show significantly higher lipophilicity, immobilized artificial membrane partitioning, AGP binding and Caco‐2 permeability compared with glucosides. However, human serum albumin binding was very high for all investigated compounds. Furthermore, a good correlation between experimentally obtained chromatographic parameters and in silico prediction was obtained for lipophilicity and human serum albumin binding, while the somewhat greater difference was obtained for AGP binding and Caco‐2 permeability. 相似文献
998.
Dr. Liqiang Wang Dr. Liu Deng Prof. You-Nian Liu 《Chemistry (Weinheim an der Bergstrasse, Germany)》2019,25(4):904-912
Nanoscale metal sulfides are of tremendous potential in biomedicine. Generally, the properties and performances of metal sulfide nanoparticles (NPs) are highly related to their structures, sizes and morphologies. Recently, a strategy of using sulfur-containing protein–metal-ion networks for preparing metal sulfide embedded nanocomposites was proposed. Within the networks, proteins can play multiple roles to drive the transformation of these networks into protein-encapsulated metal sulfide NPs with ultrasmall size and defined structure (as both a template and a sulfur provider) or metal sulfide NP–protein hydrogels with injecting and self-healing properties (as a template, a sulfur provider, and a gelator) in a controlled manner. In this Concept, the synthesis strategy, the formation mechanism, and the biomedical applications of the gained nanocomposites are presented. Moreover, the challenges and opportunities of using protein–metal ion networks to construct functional materials for biomedical applications are analyzed. 相似文献
999.
Dr. Pedro M. S. D. Cal Dr. Raquel F. M. Frade Prof. Carlos Cordeiro Dr. Pedro M. P. Gois 《Chemistry (Weinheim an der Bergstrasse, Germany)》2015,21(22):8182-8187
Iminoboronates have been utilized to successfully install azide and alkyne bioorthogonal functions on proteins, which may then be further reacted with their bioorthogonal counterparts. These constructs were also used to add polyethylene glycol (PEG) to insulin, a modification which has been shown to be reversible in the presence of fructose. Finally, iminoboronates were used to assemble a folic acid/paclitaxel small‐molecule/drug conjugate in situ with an IC50 value of 20.7 nM against NCI‐H460 cancer cells and negligible cytotoxicity against the CRL‐1502 noncancer cells. 相似文献
1000.
Post-translational methylation, discovered more than half a century ago, encodes information in the form of a structural modification on a peptide or protein. The addition of a CH3 group is one of the most subtle covalent modifications that exist in biology. In spite of this, recent years have revealed the many profound functional effects that arise from protein methylation in the cell. In an effort to open the doors to new assays and detection methods that would enable new basic and applied research into methylation pathways, chemical agents that can recognise and bind to methylated sites are now being pursued. In this review, we describe the supramolecular approaches to the recognition of methylated amino acids, peptides and proteins that have arisen in the last few years. 相似文献