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991.
Kasper P. Lundquist Dr. Vipul Panchal Prof. Charlotte H. Gotfredsen Prof. Ruth Brenk Prof. Mads H. Clausen 《ChemMedChem》2021,16(17):2588-2603
Rapid development within the fields of both fragment-based drug discovery (FBDD) and medicinal targeting of RNA provides possibilities for combining technologies and methods in novel ways. This review provides an overview of fragment-based screening (FBS) against RNA targets, including a discussion of the most recently used screening and hit validation methods such as NMR spectroscopy, X-ray crystallography, and virtual screening methods. A discussion of fragment library design based on research from small-molecule RNA binders provides an overview on both the currently limited guidelines within RNA-targeting fragment library design, and future possibilities. Finally, future perspectives are provided on screening and hit validation methods not yet used in combination with both fragment screening and RNA targets. 相似文献
992.
N. Jawahar P. Aravindan Dr S. G. Ponnambalam L. N. Raghavendra 《The International Journal of Advanced Manufacturing Technology》1998,14(7):514-538
The economy of production in flexible manufacturing systems (FMS) depends mainly on how effectively the production is planned and how the resources are used. This requires efficient and dynamic factory scheduling and control procedures. This paper addresses two knowledge-based scheduling schemes (work cell attribute oriented dynamic schedulers WCAODSs) to control the flow of parts efficiently in real-time for FMS in which the part-mix varies continually with the planning horizon. The present work employs a hybrid optimisation approach in the generalised A1 framework. A genetic algorithm that provides an optimal combination of a set of priority dispatching rules, one for each work cell WC (WCwisepdr set), for each of the problem instances characterised by their WC attributes, is used for generating examples. The WC attributes reflect the information about the operating environment of each individual WC. Two inductive learning algorithms are employed to learn the examples, and scheduling rules are formulated as a knowledge base. The learning algorithms employed are: the Genetic CID3 (Continuous Interactive Dichotomister3 algorithm extended with genetic program for weight optimisation) and the Classification Decision Tree algorithm. The knowledge base obtained through the above learning schemes generates robust and effective schedules intelligently with respect to the part-mix changes in real-time, for makespan criteria. The comparison made with a GA-based scheduling methodology shows that WCAODSs provide solutions closer to the optimum. 相似文献
993.
Seraphim Papanikolaou Dr. Afroditi Chatzifragkou Stylianos Fakas Maria Galiotou‐Panayotou Michael Komaitis Jean‐Marc Nicaud George Aggelis 《European Journal of Lipid Science and Technology》2009,111(12):1221-1232
The biochemical behavior of wild‐type or genetically modified (presenting decreased expression of intracellular acyl‐CoA oxidases) Yarrowia lipolytica strains cultivated on commercial glucose was studied. Flask nitrogen‐limited cultures were performed favoring the production of organic acids (and potentially the accumulation of lipid). Nitrogen depletion induced secretion of citric acid, while intracellular lipid was not produced in high quantities. Maximum total citric acid up to 49 g/L (yield 0.85 g/g glucose) was produced. In some of the wild‐type strains, an increase of glucose in the medium also induced noticeable production of acetic acid. Increasing the amount of added glucose led to an increase in the total lipid quantity (%) produced, although in the stationary growth phase the concentration of lipid declined, indicating lipid degradation even for the genetically modified strains. Total lipid amount did not exceed the value of 14%, while neutral fractions increased with increase in glucose concentration. In all cases, the total microbial lipids and major lipid fractions were composed of C16 and C18 (principally unsaturated) fatty acids. Finally, in several of the strains cultured in media containing a low glucose concentration, unicellular morphology was observed, while at high glucose concentrations mycelia were predominant. 相似文献
994.
15‐Methylene‐Eburnamonine Kills Leukemic Stem Cells and Reduces Engraftment in a Humanized Bone Marrow Xenograft Mouse Model of Leukemia 下载免费PDF全文
Dr. Dilini C. Gunasekara Dr. Mary M. Zheng Tara Mojtahed Dr. James R. Woods Prof. Tamer E. Fandy Dr. Mark V. Riofski Prof. Carlotta A. Glackin Prof. Hazem E. Hassan Dr. Julia Kirshner Prof. David A. Colby 《ChemMedChem》2016,11(21):2392-2397
Recent studies suggest that leukemia stem cells (LSCs) play a critical role in the initiation, propagation, and relapse of leukemia. Herein we show that (?)‐15‐methylene‐eburnamonine, a derivative of the alkaloid (?)‐eburnamonine, is cytotoxic against acute and chronic lymphocytic leukemias (ALL and CLL) and acute myelogenous leukemia (AML). The agent also decreases primary LSC frequency in vitro. The cytotoxic effects appear to be mediated via the oxidative stress pathways. Furthermore, we show that the compound kills AML, ALL, and CLL stem cells. By the use of a novel humanized bone marrow murine model of leukemia (huBM/NSG), it was found to decrease progenitor cell engraftment. 相似文献
995.
996.
Sharon N. Greenwood Dr. Rashmi S. Kulkarni Dr. Michel Mikhail Dr. Brian P. Weiser 《Chembiochem : a European journal of chemical biology》2023,24(10):e202200765
DNA repair proteins participate in extensive protein−protein interactions that promote the formation of DNA repair complexes. To understand how complex formation affects protein function during base excision repair, we used SpyCatcher/SpyTag ligation to produce a covalent complex between human uracil DNA glycosylase (UNG2) and replication protein A (RPA). Our covalent “RPA−Spy−UNG2” complex could identify and excise uracil bases in duplex areas next to ssDNA−dsDNA junctions slightly faster than the wild-type proteins, but this was highly dependent on DNA structure, as the turnover of the RPA−Spy−UNG2 complex slowed at DNA junctions where RPA tightly engaged long ssDNA sections. Conversely, the enzymes preferred uracil sites in ssDNA where RPA strongly enhanced uracil excision by UNG2 regardless of ssDNA length. Finally, RPA was found to promote UNG2 excision of two uracil sites positioned across a ssDNA−dsDNA junction, and dissociation of UNG2 from RPA enhanced this process. Our approach of ligating together RPA and UNG2 to reveal how complex formation affects enzyme function could be applied to examine other assemblies of DNA repair proteins. 相似文献
997.
998.
A New SiF–Dipropargyl Glycerol Scaffold as a Versatile Prosthetic Group to Design Dimeric Radioligands: Synthesis of the [18F]BMPPSiF Tracer to Image Serotonin Receptors 下载免费PDF全文
Dr. Puja Panwar Hazari Dr. Jurgen Schulz Delphine Vimont Nidhi Chadha Prof. Michele Allard Dr. Magali Szlosek‐Pinaud Prof. Eric Fouquet Dr. Anil Kumar Mishra 《ChemMedChem》2014,9(2):337-349
A novel SiX–dipropargyl glycerol scaffold (X: H, F, or 18F) was developed as a versatile prosthetic group that provides technical advantages for the preparation of dimeric radioligands based on silicon fluoride acceptor pre‐ or post‐labeling with fluorine‐18. Rapid conjugation with the prosthetic group takes place in microwave‐assisted click conjugation under mild conditions. Thus, a bivalent homodimeric SiX–dipropargyl glycerol derivatized radioligand, [18F]BMPPSiF, with enhanced affinity was developed by using click conjugation. High uptake of the radioligand was demonstrated in 5‐HT1A receptor‐rich regions in the brain with positron emission tomography. Molecular docking studies (rigid protein–flexible ligand) of BMPPSiF and known antagonists (WAY‐100635, MPPF, and MefWAY) with monomeric, dimeric, and multimeric 5‐HT1A receptor models were performed, with the highest G score obtained for docked BMPPSiF: ?6.766 as compared with all three antagonists on the monomeric model. Multimeric induced‐fit docking was also performed to visualize the comparable mode of binding under in vivo conditions, and a notably improved G score of ?8.455 was observed for BMPPSiF. These data directly correlate the high binding potential of BMPPSiF with the bivalent binding mode obtained in the biological studies. The present study warrants wide application of the SiX–dipropargyl glycerol prosthetic group in the development of ligands for imaging with enhanced affinity markers for specific targeting based on peptides, nucleosides, and lipids. 相似文献
999.
Dr. Roman J. Lichtenecker Dr. Bernhard Ellinger Dr. Hong‐Mei Han Kirtikumar B. Jadhav Dr. Sascha Baumann Dr. Oliwia Makarewicz Dr. Markus Grabenbauer Prof. Dr. Hans‐Dieter Arndt 《Chembiochem : a European journal of chemical biology》2013,14(18):2492-2499
Growing resistance to antibiotics, as well as newly emerging pathogens, stimulate the investigation of antimicrobial peptides (AMPs) as therapeutic agents. Here, we report a new library design concept based on a stochastic distribution of natural AMP amino acid sequences onto half‐length synthetic peptides. For these compounds, a non‐natural motif of alternating D ‐ and L ‐backbone stereochemistry of the peptide chain predisposed for β‐helix formation was explored. Synthetic D ‐/L ‐peptides with permuted half‐length sequences were delineated from a full‐length starter sequence and covalently recombined to create two‐dimensional compound arrays for antibacterial screening. Using the natural AMP magainin as a seed sequence, we identified and iteratively optimized hit compounds showing high antimicrobial activity against Gram‐positive and Gram‐negative bacteria with low hemolytic activity. Cryo‐electron microscopy characterized the membrane‐associated mechanism of action of the new D ‐/L ‐peptide antibiotics. 相似文献
1000.
Alexander Kleinschek Christian Meyners Eros Digiorgio Prof. Dr. Claudio Brancolini Prof. Dr. Franz‐Josef Meyer‐Almes 《ChemMedChem》2016,11(23):2598-2606
Specific inhibition of histone deacetylase 8 (HDAC8) has been suggested as a promising option for the treatment of neuroblastoma and T‐cell malignancies. A novel class of highly potent and selective HDAC8 inhibitors with a pyrimido[1,2‐c][1,3]benzothiazin‐6‐imine scaffold was studied that is completely different from the traditional concept of HDAC inhibitors comprising a zinc binding group (ZBG), in most cases a hydroxamate group, a spacer, and a capping group that may interact with the surface of the target protein. Although lacking a ZBG, some of the new compounds were shown to have outstanding potency against HDAC8 in the single‐digit nanomolar range. The pyrimido[1,2‐c][1,3]benzothiazin‐6‐imines also inhibited the growth of solid and hematological tumor cells. The small size and beneficial physicochemical properties of the novel HDAC inhibitor class underline the high degree of drug likeness. This and the broad structure–activity relationship suggest great potential for the further development of compounds with the pyrimido[1,2‐c][1,3]benzothiazin‐6‐imine scaffold into innovative and highly effective therapeutic drugs against cancer. 相似文献