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101.
Ionizable Amino‐Polyesters Synthesized via Ring Opening Polymerization of Tertiary Amino‐Alcohols for Tissue Selective mRNA Delivery
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Piotr S. Kowalski Umberto Capasso Palmiero Yuxuan Huang Arnab Rudra Robert Langer Daniel G. Anderson 《Advanced materials (Deerfield Beach, Fla.)》2018,30(34)
The utility of messenger RNA (mRNA) as a therapy is gaining a broad interest due to its potential for addressing a wide range of diseases, while effective delivery of mRNA molecules to various tissues still poses a challenge. This study reports on the design and characterization of new ionizable amino‐polyesters (APEs), synthesized via ring opening polymerization (ROP) of lactones with tertiary amino‐alcohols that enable tissue and cell type selective delivery of mRNA. With a diverse library of APEs formulated into lipid nanoparticles (LNP), structure‐activity parameters crucial for efficient transfection are established and APE‐LNPs are identified that can preferentially home to and elicit effective mRNA expression with low in vivo toxicity in lung endothelium, liver hepatocytes, and splenic antigen presenting cells, including APE‐LNP demonstrating nearly tenfold more potent systemic mRNA delivery to the lungs than vivo‐jetPEI. Adopting tertiary amino‐alcohols to initiate ROP of lactones allows to control polymer molecular weight and obtain amino‐polyesters with narrow molecular weight distribution, exhibiting batch‐to‐batch consistency. All of which highlight the potential for clinical translation of APEs for systemic mRNA delivery and demonstrate the importance of employing controlled polymerization in the design of new polymeric nanomaterials to improve in vivo nucleic acid delivery. 相似文献
102.
Martha L. Carlson Mazur Jeff Schaeffer Jennifer E. Granneman Natalie Goldstrohm Faith A. Fitzpatrick James H. Larson Paul C. Reneau Kurt P. Kowalski Paul W. Seelbach 《Journal of Great Lakes research》2019,45(3):651-663
Rivermouth ecosystems in the Laurentian Great Lakes represent complex hydrologic mixing zones where lake and river water combine to form biologically productive areas that are functionally similar to marine estuaries. As urban, industrial, shipping, and recreational centers, rivermouths are the focus of human interactions with the Great Lakes and, likewise, may represent critical habitat for larval fish and other biota. The hydrology and related geomorphology in these deltaic systems form the basis for ecosystem processes and wetland habitat structure but are poorly understood. To this end, we examined hydrogeomorphic structure and lake-tributary mixing in three rivermouths of intermediate size using water chemistry, stable isotopes, and current profiling over a five-month period. In rivermouths of this size, the maximum depth of the rivermouth ecosystem influenced water mixing, with temperature-related, density-dependent wedging and layering that isolated lake water below river water occurring in deeper systems. The inherent size of the rivermouth ecosystem, local geomorphology, and human modifications such as shoreline armoring and dredging influenced mixing by altering the propensity for density differences to occur. The improved scientific understanding and framework for characterizing hydrogeomorphic processes in Great Lakes rivermouths across a disturbance gradient is useful for conservation, management, restoration, and protection of critical habitats needed by native species. 相似文献
103.
Front Cover: [Carboxyl‐11C]Labelling of Four High‐Affinity cPLA2α Inhibitors and Their Evaluation as Radioligands in Mice by Positron Emission Tomography (ChemMedChem 2/2018)
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104.
[Carboxyl‐11C]Labelling of Four High‐Affinity cPLA2α Inhibitors and Their Evaluation as Radioligands in Mice by Positron Emission Tomography
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Dr. Martin J. Fisher Dr. Lindsay McMurray Dr. Shuiyu Lu Cheryl L. Morse Dr. Jeih‐San Liow Dr. Sami S. Zoghbi Aneta Kowalski George L. Tye Dr. Robert B. Innis Prof. Franklin I. Aigbirhio Dr. Victor W. Pike 《ChemMedChem》2018,13(2):138-146
Cytosolic phospholipase A2α (cPLA2α) may play a critical role in neuropsychiatric and neurodegenerative disorders associated with oxidative stress and neuroinflammation. An effective PET radioligand for imaging cPLA2α in living brain might prove useful for biomedical research, especially on neuroinflammation. We selected four high‐affinity (IC50 2.1–12 nm ) indole‐5‐carboxylic acid‐based inhibitors of cPLA2α, namely 3‐isobutyryl‐1‐(2‐oxo‐3‐(4‐phenoxyphenoxy)propyl)‐1H‐indole‐5‐carboxylic acid ( 1 ); 3‐acetyl‐1‐(2‐oxo‐3‐(4‐(4‐(trifluoromethyl)phenoxy)phenoxy)propyl)‐1H‐indole‐5‐carboxylic acid ( 2 ); 3‐(3‐methyl‐1,2,4‐oxadiazol‐5‐yl)‐1‐(2‐oxo‐3‐(4‐phenoxyphenoxy)propyl)‐1H‐indole‐5‐carboxylic acid ( 3 ); and 3‐(3‐methyl‐1,2,4‐oxadiazol‐5‐yl)‐1‐(3‐(4‐octylphenoxy)‐2‐oxopropyl)‐1H‐indole‐5‐carboxylic acid ( 4 ), for labelling in carboxyl position with carbon‐11 (t1/2=20.4 min) to provide candidate PET radioligands for imaging brain cPLA2α. Compounds [11C] 1 – 4 were obtained for intravenous injection in adequate overall yields (1.1–5.5 %) from cyclotron‐produced [11C]carbon dioxide and with moderate molar activities (70–141 GBq μmol?1) through the use of Pd0‐mediated [11C]carbon monoxide insertion on iodo precursors. Measured logD7.4 values were within a narrow moderate range (1.9–2.4). After intravenous injection of [11C] 1 – 4 in mice, radioactivity uptakes in brain peaked at low values (≤0.8 SUV) and decreased by about 90 % over 15 min. Pretreatments of the mice with high doses of the corresponding non‐radioactive ligands did not alter brain time–activity curves. Brain uptakes of radioactivity after administration of [11C] 1 to wild‐type and P‐gp/BCRP dual knock‐out mice were similar (peak 0.4 vs. 0.5 SUV), indicating that [11C] 1 and others in this structural class, are not substrates for efflux transporters. 相似文献
105.
In Vivo Delivery and Activation of Masked Fluorogenic Hydrolase Substrates by Endogenous Hydrolases in C. elegans
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Shataakshi Dube Hitesh Dube Nicole B. Green Erik M. Larsen Alex White R. Jeremy Johnson Jennifer R. Kowalski 《Chembiochem : a European journal of chemical biology》2017,18(18):1807-1813
Protein expression and localization are often studied in vivo by tagging molecules with green fluorescent protein (GFP), yet subtle changes in protein levels are not easily detected. To develop a sensitive in vivo method to amplify fluorescence signals and allow cell‐specific quantification of protein abundance changes, we sought to apply an enzyme‐activated cellular fluorescence system in vivo by delivering ester‐masked fluorophores to Caenorhabditis elegans neurons expressing porcine liver esterase (PLE). To aid uptake into sensory neuron membranes, we synthesized two novel fluorogenic hydrolase substrates with long hydrocarbon tails. Recombinant PLE activated these fluorophores in vitro. In vivo activation occurred in sensory neurons, along with potent activation in intestinal lysosomes quantifiable by imaging and microplate and partially attributable to gut esterase 1 (GES‐1) activity. These data demonstrate the promise of biorthogonal hydrolases and their fluorogenic substrates as in vivo neuronal imaging tools and for characterizing endogenous C. elegans hydrolase substrate specificities. 相似文献
106.
The effect of counter anions on corrosion resistance of steel covered by bi-layered polypyrrole film
The bi-layered polypyrrole (PPy) coatings were investigated for corrosion prevention of a carbon steel. The inner layer was doped with the Keggin structure anions of (PMo12) and anions for stabilization of the passive oxide film at the metal-polymer interface, and the outer layer was doped with four organic anions of dihydroxynaphthalenedisulfonate (DHNDS), naphthalenedisulfonate (NDS), anthraquinonedisulfonate (AnqDS) or dodecylsulfate (DoS) for inhibition of the decomposition and release of PMo12. The corrosion tests were performed in 3.5 wt.% NaCl aqueous solution. The corrosion resistance of the steels covered by the bi-layered PPy films was found in the following order: PPy-PMo12/PPy-DHNDS < PPy-PMo12/PPy-NDS < PPy-PMo12/AnqDS < PPy-PMo12/PPy-DoS. The performance of corrosion protection related to the oxidized state of the polymer was discussed. 相似文献
107.
108.
Ozan Nazm Çiftçi Bolesaw Kowalski Fahrettin Göü Sibel Fadlolu 《Journal of food science》2009,74(4):E184-E190
ABSTRACT: A cocoa butter (CB)–like fat was produced in a packed bed enzyme reactor using sn -1,3 specific lipase, and its blends with CB were prepared at different ratios (CB: CB-like fat; 100: 0, 90: 10, 80: 20, 70: 30, 60: 40, 50: 50, 0: 100). The oxidation kinetics of CB: CB-like fat blends was studied by differential scanning calorimeter (DSC). Samples were heated in DSC at different temperatures (130, 140, 150, 160 °C) under 100 mL/min oxygen. From DSC exotherms, oxidation induction times (OIT) were determined and used for the assessment of the oxidative stabilities of the blends. Oxidation kinetics parameters (activation energy, Ea ; preexponential factor, Z ; and oxidation rate constant, k ) were calculated. In general, it has been observed that above 110 °C increasing the ratio of CB-like fat in the blend increased the k value with increasing temperature. It has been observed that for all blends the increase in k value with temperature was significant ( P < 0.05). Increasing CB-like fat ratio in the blend decreased the content of major TAGs (1,3-dipalmitoyl-2-oleoyl-glycerol [POP]; 1[3]-palmitoyl-3[1]stearoyl-2-oleoyl-glycerol [POS]; 1,3-distearoyl-2-oleoyl-glycerol [SOS]), and decreased the oxidative stability of the blends. 相似文献
109.
Using synchrotron radiation, we have measured the efficiency at an angle of incidence of 10 degrees of a holographic ion-etched spherical blazed grating and three of its fourth-generation replicas. The measured efficiency profile of replicas 1 and 3 prior to multilayer coating oscillated from thin-film interference produced by the replicas' Al/Al2O3/SiO2 structure. A Mo2C/Si multilayer coating was applied to the master grating and replicas 1 and 2. After coating, the maximum grating efficiency occurred in the -2nd order and the maximum values were 12.4% at 143.8 angstroms for the master and 11.6% at 145.2 angstroms for replicas 1 and 2. On the basis of measurements obtained after coating, the derived groove efficiency was 22.2% for the master, 19.4% for replica 1, and 19.3% for replica 2. The groove efficiency of the uncoated replica 3 was 24.3% at 142.5 angstroms. We find that the replicas are reasonably faithful copies of the ion-etched master, and models based on measured atomic force microscope groove profiles are in general agreement with measured results. However, subtle issues remain regarding the widths of the peak order profile and the location of its maximum wavelength. 相似文献
110.