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991.
Rachel Anne P. Valenzuela Scott R. Suter Alexi A. Ball‐Jones Dr. José M. Ibarra‐Soza Yuxuan Zheng Prof. Dr. Peter A. Beal 《Chembiochem : a European journal of chemical biology》2015,16(2):262-267
Immune stimulation triggered by siRNAs is one of the major challenges in the development of safe RNAi‐based therapeutics. Within an immunostimulatory siRNA sequence, this hurdle is commonly addressed by using ribose modifications (e.g., 2′‐OMe or 2′‐F), which results in decreased cytokine production. However, as immune stimulation by siRNAs is a sequence‐dependent phenomenon, recognition of the nucleobases by the trigger receptor(s) is also likely. Here, we use the recently published crystal structures of Toll‐like receptor 8 (TLR8) bound to small‐molecule agonists to generate computational models for ribonucleotide binding by this immune receptor. Our modeling suggested that modification of either the Watson–Crick or Hoogsteen face of adenosine would disrupt nucleotide/TLR8 interactions. We employed chemical synthesis to alter either the Watson–Crick or Hoogsteen face of adenosine and evaluated the effect of these modifications in an siRNA guide strand by measuring the immunostimulatory and RNA interference properties. For the siRNA guide strand tested, we found that modifying the Watson–Crick face is generally more effective at blocking TNFα production in human peripheral blood mononuclear cells (PBMCs) than modification at the Hoogsteen edge. We also observed that modifications near the 5′‐end were more effective at blocking cytokine production than those placed at the 3′‐end. This work advances our understanding of how chemical modifications can be used to optimize siRNA performance. 相似文献
992.
Hydrogen‐Bonding‐Driven Enantioselective Resolution against the Kazlauskas Rule To Afford γ‐Amino Alcohols by Candida rugosa Lipase 下载免费PDF全文
Bora Min Jeemin Park Yong‐Kyun Sim Dr. Suhyun Jung Seong‐Ho Kim Dr. Jae Kwang Song Dr. Bum Tae Kim Prof. Sang Youn Park Prof. Jaesook Yun Prof. Seongsoon Park Dr. Hyuk Lee 《Chembiochem : a European journal of chemical biology》2015,16(1):77-82
Most lipases resolve secondary alcohols in accordance with the “Kazlauskas rule” to give the R enantiomers. In a similar manner to other lipases, Candida rugosa lipase (CRL) exhibits R enantioselectivity towards heptan‐2‐ol, although the enantiomeric ratio (E) is low (E=1.6). However, unexpected enantioselectivity (i.e., S enantioselectivity, E=58) of CRL towards 4‐(tert‐butoxycarbonylamino)butan‐2‐ol, which has a similar chain length to heptan‐2‐ol, has been observed. To develop a deeper understanding of the molecular basis for this unusual enantioselectivity, we have conducted a series of molecular modeling and substrate engineering experiments. The results of these computational and experimental analyses indicated that a hydrogen bond between the Ser450 residue and the nitrogen atom of the carbamate group is critical to stabilize the transition state of the S enantiomer. 相似文献
993.
Jekaterina Hermane Ilona Bułyszko Dr. Simone Eichner Dr. Florenz Sasse Wera Collisi Prof. Dr. Antti Poso Emilia Schax Dr. Johanna‐Gabriela Walter Prof. Dr. Thomas Scheper Dr. Klaus Kock Prof. Dr. Christian Herrmann Dr. Pooyan Aliuos Prof. Dr. Günter Reuter Priv.‐Doz. Dr. Carsten Zeilinger Prof. Dr. Andreas Kirschning 《Chembiochem : a European journal of chemical biology》2015,16(2):302-311
Streptomyces hygroscopicus is a natural producer of geldanamycin. Mutasynthetic supplementation of an AHBA‐blocked mutant with all possible monofluoro 3‐aminobenzoic acids provided new fluorogeldanamycins. These showed strong antiproliferative activity and inhibitory effects on human heat shock protein Hsp90. Binding to Hsp90 in the low nanomolar range was determined from molecular modelling, AFM analysis and by calorimetric studies. 相似文献
994.
Thioether Analogues of Disulfide‐Bridged Cyclic Peptides Targeting Death Receptor 5: Conformational Analysis,Dimerisation and Consequences for Receptor Activation 下载免费PDF全文
Dr. Karolina Pulka‐Ziach Dr. Valeria Pavet Neila Chekkat Dr. Karine Estieu‐Gionnet Roman Rohac Dr. Marie‐Charlotte Lechner Dr. Cristian R. Smulski Dr. Gabrielle Zeder‐Lutz Dr. Danièle Altschuh Dr. Hinrich Gronemeyer Prof. Dr. Sylvie Fournel Dr. Benoit Odaert Dr. Gilles Guichard 《Chembiochem : a European journal of chemical biology》2015,16(2):293-301
Cyclic peptides containing redox‐stable thioether bridges might provide a useful alternative to disulfide‐bridged bioactive peptides. We report the effect of replacing the disulfide bridge with a lanthionine linkage in a 16‐mer cyclic peptide that binds to death receptor 5 (DR5, TRAIL‐R2). Upon covalent oligomerisation, the disulfide‐bridged peptide has previously shown similar behaviour to that of TNF‐related apoptosis inducing ligand (TRAIL), by selectively triggering the DR5 cell death pathway. The structural and biological properties of the DR5‐binding peptide and its desulfurised analogue were compared. Surface plasmon resonance (SPR) data suggest that these peptides bind DR5 with comparable affinities. The same holds true for dimeric versions of these peptides: the thioether is able to induce DR5‐mediated apoptosis of BJAB lymphoma and tumorigenic BJELR cells, albeit to a slightly lower extent compared to its disulfide homologue. NMR analysis revealed subtle variation in the conformations of the two peptides and suggests that the thioether peptide is slightly less folded than its disulfide homologue. These observations could account for the different capability of the two dimers to cluster DR5 receptors on the cell surface and to trigger apoptosis. Nevertheless, our results suggest that the thioether peptide is a potential candidate for evaluation in animal models. 相似文献
995.
Inhibitors of Polyhydroxyalkanoate (PHA) Synthases: Synthesis,Molecular Docking,and Implications 下载免费PDF全文
Dr. Wei Zhang Dr. Chao Chen Ruikai Cao Dr. Leila Maurmann Prof. Ping Li 《Chembiochem : a European journal of chemical biology》2015,16(1):156-166
Polyhydroxyalkanoate (PHA) synthases (PhaCs) catalyze the formation of biodegradable PHAs that are considered to be ideal alternatives to non‐biodegradable synthetic plastics. However, study of PhaCs has been challenging because the rate of PHA chain elongation is much faster than that of initiation. This difficulty, along with lack of a crystal structure, has become the main hurdle to understanding and engineering PhaCs for economical PHA production. Here we report the synthesis of two carbadethia CoA analogues—sT‐CH2‐CoA ( 26 a ) and sTet‐CH2‐CoA ( 26 b )—as well as sT‐aldehyde (saturated trimer aldehyde, 29 ), as new PhaC inhibitors. Study of these analogues with PhaECAv revealed that 26 a / b and 29 are competitive and mixed inhibitors, respectively. Both the CoA moiety and extension of PHA chain will increase binding affinity; this is consistent with our docking study. Estimation of the Kic values of 26 a and 26 b predicts that a CoA analogue incorporating an octameric hydroxybutanoate (HB) chain might facilitate the formation of a kinetically well‐behaved synthase. 相似文献
996.
Dr. Naoki Umezawa Yuhei Horai Dr. Yuki Imamura Makoto Kawakubo Mariko Nakahira Dr. Nobuki Kato Akira Muramatsu Prof. Dr. Yuko Yoshikawa Prof. Dr. Kenichi Yoshikawa Prof. Dr. Tsunehiko Higuchi 《Chembiochem : a European journal of chemical biology》2015,16(12):1811-1819
A versatile solid‐phase approach based on peptide chemistry was used to construct four classes of structurally diverse polyamines with modified backbones: linear, partially constrained, branched, and cyclic. Their effects on DNA duplex stability and structure were examined. The polyamines showed distinct activities, thus highlighting the importance of polyamine backbone structure. Interestingly, the rank order of polyamine ability for DNA compaction was different to that for their effects on circular dichroism and melting temperature, thus indicating that these polyamines have distinct effects on secondary and higher‐order structures of DNA. 相似文献
997.
Structural Insight into the Complex of Ferredoxin and [FeFe] Hydrogenase from Chlamydomonas reinhardtii 下载免费PDF全文
Dr. Sigrun Rumpel Judith F. Siebel Mamou Diallo Dr. Christophe Farès Dr. Edward J. Reijerse Prof. Wolfgang Lubitz 《Chembiochem : a European journal of chemical biology》2015,16(11):1663-1669
The transfer of photosynthetic electrons by the ferredoxin PetF to the [FeFe] hydrogenase HydA1 in the microalga Chlamydomonas reinhardtii is a key step in hydrogen production. Electron delivery requires a specific interaction between PetF and HydA1. However, because of the transient nature of the electron‐transfer complex, a crystal structure remains elusive. Therefore, we performed protein–protein docking based on new experimental data from a solution NMR spectroscopy investigation of native and gallium‐substituted PetF. This provides valuable information about residues crucial for complex formation and electron transfer. The derived complex model might help to pinpoint residue substitution targets for improved hydrogen production. 相似文献
998.
Hyoung Eun Bae Prof. Kamil Gotfryd Jennifer Thomas Hazrat Hussain Muhammad Ehsan Juyeon Go Prof. Claus J. Loland Dr. Bernadette Byrne Prof. Pil Seok Chae 《Chembiochem : a European journal of chemical biology》2015,16(10):1454-1459
Detergents are an absolute requirement for studying the structure of membrane proteins. However, many conventional detergents fail to stabilise denaturation‐sensitive membrane proteins, such as eukaryotic proteins and membrane protein complexes. New amphipathic agents with enhanced efficacy in stabilising membrane proteins will be helpful in overcoming the barriers to studying membrane protein structures. We have prepared a number of deoxycholate‐based amphiphiles with carbohydrate head groups, designated deoxycholate‐based glycosides (DCGs). These DCGs are the hydrophilic variants of previously reported deoxycholate‐based N‐oxides (DCAOs). Membrane proteins in these agents, particularly the branched diglucoside‐bearing amphiphiles DCG‐1 and DCG‐2, displayed favourable behaviour compared to previously reported parent compounds (DCAOs) and conventional detergents (LDAO and DDM). Given their excellent properties, these agents should have significant potential for membrane protein studies. 相似文献
999.
Conversion of a Mono‐ and Diacylglycerol Lipase into a Triacylglycerol Lipase by Protein Engineering 下载免费PDF全文
Dr. Dongming Lan Dr. Grzegorz Maria Popowicz Dr. Ioannis V. Pavlidis Pengfei Zhou Prof. Dr. Uwe T. Bornscheuer Prof. Dr. Yonghua Wang 《Chembiochem : a European journal of chemical biology》2015,16(10):1431-1434
Despite the fact that most lipases are believed to be active against triacylglycerides, there is a small group of lipases that are active only on mono‐ and diacylglycerides. The reason for this difference in substrate scope is not clear. We tried to identify the reasons for this in the lipase from Malassezia globosa. By protein engineering, and with only one mutation, we managed to convert this enzyme into a typical triacylglycerol lipase (the wild‐type lipase does not accept triacylglycerides). The variant Q282L accepts a broad spectrum of triacylglycerides, although the catalytic behavior is altered to some extent. From in silico analysis it seems that specific hydrophobic interactions are key to the altered substrate specificity. 相似文献
1000.
Lalisa Stutts Prof. Aaron P. Esser‐Kahn 《Chembiochem : a European journal of chemical biology》2015,16(12):1744-1748
The spatial and temporal aspects of immune cell signaling are key parameters in defining the magnitude of an immune response. Toll‐like receptors (TLRs) on innate immune cells are important in the early detection of pathogens and initiation of an immune response. Controlling the spatial and temporal signaling of TLRs would enable further study of immune synergies and assist in the development of new vaccines. Here, we show a light‐based method for the spatial control of TLR4 signaling. A TLR4 agonist, pyrimido[5,4‐b]indole, was protected with a cage at a position critical for receptor binding. This afforded a photocontrollable agonist that was inactive while caged, yet effected NF‐κB activity in cells following UV photocontrolled deprotection. We demonstrated spatial control of NF‐κB activation within a population of cells by treating all cells with the caged TLR4 agonist and constraining light exposure and consequent activation to a region of interest. 相似文献