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21.
Bioavailability Studies and in vitro Profiling of the Selective Excitatory Amino Acid Transporter Subtype 1 (EAAT1) Inhibitor UCPH‐102 下载免费PDF全文
Dr. Isabell Haym Dr. Tri H. V. Huynh Dr. Stinne W. Hansen Dr. Martin H. F. Pedersen Dr. Josep A. Ruiz Dr. Mette N. Erichsen Dr. Mikko Gynther Walden E. Bjørn‐Yoshimoto Dr. Bjarke Abrahamsen Dr. Jesper F. Bastlund Dr. Christoffer Bundgaard Anette L. Eriksen Prof. Anders A. Jensen Prof. Lennart Bunch 《ChemMedChem》2016,11(4):403-419
Although the selective excitatory amino acid transporter subtype 1 (EAAT1) inhibitor UCPH‐101 has become a standard pharmacological tool compound for in vitro and ex vivo studies in the EAAT research field, its inability to penetrate the blood–brain barrier makes it unsuitable for in vivo studies. In the present study, per os (p.o.) administration (40 mg kg?1) of the closely related analogue UCPH‐102 in rats yielded respective plasma and brain concentrations of 10.5 and 6.67 μm after 1 h. Three analogue series were designed and synthesized to improve the bioavailability profile of UCPH‐102, but none displayed substantially improved properties in this respect. In vitro profiling of UCPH‐102 (10 μm ) at 51 central nervous system targets in radioligand binding assays strongly suggests that the compound is completely selective for EAAT1. Finally, in a rodent locomotor model, p.o. administration of UCPH‐102 (20 mg kg?1) did not induce acute effects or any visible changes in behavior. 相似文献
22.
Cosmin Popescu Björn Täljsten Thomas Blanksvärd Lennart Elfgren 《Structure and Infrastructure Engineering》2019,15(7):912-924
Routine bridge inspections usually consist of visual observations. These inspections are time-consuming and subjective. There is a need to identify new inspection techniques for infrastructure that reduce traffic disturbance, and improve the efficiency and reliability of the acquired data. This study compared the performance of three different imaging technologies for the three-dimensional (3D) geometric modeling of existing structures: terrestrial laser scanning, close-range photogrammetry, and infrared scanning. Each technology was used to assess six existing concrete railway bridges. The technologies were compared in terms of geometric deviations, visualization capabilities, the level of the inspector’s experience, and degree of automation. The results suggest that all methods investigated can be used to create 3D models, however, with different level of completeness. Measurements such as span length, deck widths, etc. can be extracted with good accuracy. Although promising, a full off-site inspection is currently not feasible as some areas of the bridges were difficult to capture mainly due to restricted access and narrow spaces. Measurements based on terrestrial laser scanning were closer to the reality compared to photogrammetry and infrared scanning. The study indicates the no special training is needed for photogrammetry and infrared scanning to generate a 3D geometric model. 相似文献
23.
Dr. Lennart Brewitz Dr. Jos J. A. G. Kamps Dr. Petra Lukacik Claire Strain-Damerell Yilin Zhao Dr. Anthony Tumber Tika R. Malla Dr. Allen M. Orville Dr. Martin A. Walsh Prof. Dr. Christopher J. Schofield 《ChemMedChem》2022,17(9):e202200016
The two SARS-CoV-2 proteases, i. e. the main protease (Mpro) and the papain-like protease (PLpro), which hydrolyze the viral polypeptide chain giving functional non-structural proteins, are essential for viral replication and are medicinal chemistry targets. We report a high-throughput mass spectrometry (MS)-based assay which directly monitors PLpro catalysis in vitro. The assay was applied to investigate the effect of reported small-molecule PLpro inhibitors and selected Mpro inhibitors on PLpro catalysis. The results reveal that some, but not all, PLpro inhibitor potencies differ substantially from those obtained using fluorescence-based assays. Some substrate-competing Mpro inhibitors, notably PF-07321332 (nirmatrelvir) which is in clinical development, do not inhibit PLpro. Less selective Mpro inhibitors, e. g. auranofin, inhibit PLpro, highlighting the potential for dual PLpro/Mpro inhibition. MS-based PLpro assays, which are orthogonal to widely employed fluorescence-based assays, are of utility in validating inhibitor potencies, especially for inhibitors operating by non-covalent mechanisms. 相似文献
24.
The aim of the present study was to investigate the influence of partially hydrogenated vegetable and marine oils on membrane
composition and function of liver microsomes and platelets with particular reference to the metabolism of linoleic acid and
the production of arachidonic acid metabolites. Four groups of male weanling rats were fed linoleic acid supplemented diets
containing 20% (w/w) of partially hydrogenated low erucic acid rapeseed oil (HLRSO), partially hydrogenated herring oil (HHO),
olive oil (OO) and trierucin + triolein (TE) for 10 weeks. An additional two groups were fed partially hydrogenated low erucic
acid rapeseed oil and partially hydrogenated herring oil without linoleic acid supplementation (HLRSO- and HHO-, respectively).
Substantial amounts oftrans fatty acids were incorporated into liver microsomes (12.6% in group HLRSO) and platelets (7.0% in group HLRSO-). This incorporation
was not dependent on the dietary linoleic acid level. Hepatic microsomal Δ5-desaturase activity was significantly increased after HLRSO feeding compared to OO feeding. Δ6-Desaturase activity did not vary in the linoleic acid supplemented groups. Both Δ5- and Δ6-desaturase activities were significantly increased in groups without linoleic acid supplementation.
Docosenoic acid was incorporated into platelet phospholipids in contrast to liver microsomes. In the platelet, docosenoic
acid seemed to have a special preference for phosphatidylserine. Very small amounts were incorporated into platelet phosphatidylinositol.
Feeding diets HLRSO, HHO and OO did not influence rat platelet cyclooxygenase or 12-lipoxygenase activity. Platelets from
rats fed TE, however, produced significantly less 12-hydroxy-5,8,10,14-eicosatetraenoic acid (12-HETE) than platelets from
rats fed OO. Feeding of HLRSO- and HHO- resulted in a significantly diminished production of the arachidonic acid metabolites
12-HETE, 12-hydroxy-5,8,10-heptadecatrienoic acid (HHT) and 6-keto-prostaglandin F1α in stimulated platelets and aorta. Thus, high dietary levels oftrans isomers of monoenoic acids do not interfere with platelet cyclooxygenase or lipoxygenase activity provided sufficient amounts
of linoleic acid are available. 相似文献
25.
Un jet à très haute pression d'eau et d'air en même temps qu'une injection de pâte de ciment est en train de ?révolutionner? la pratique des injections dans le sol et consolidation des fondations. Cette technique développée en Suède est brièvement exposée ici. L'article s'appuie sur une note résumée publiée par le Conseil suédois pour la recherche sur la construction. 相似文献
26.
The influence of contact zone configuration on the flow structure in a dissolved air flotation pilot plant 总被引:2,自引:0,他引:2
The dissolved air flotation process is used in water and wastewater treatment. Among many parameters the fluid dynamics determine the capacity of the process. The contact zone is assumed to be important for the removal function, as it is believed to be the location for the aggregation of bubbles and flocs. This paper presents an experimental study on the flow structure in a contact zone of a DAF pilot tank and the influence of contact zone configuration. The flow structure in the contact zone was examined for different horizontal lengths of the zone and for different heights and inclinations of the shaft wall. The hydraulic surface loading was 11 m/h over the total tank surface area and the recycle rate was constant at 10% of the main flow. The examined hydraulic surface loading over the contact zone ranged from 40 to 98 m/h. Water velocities in the longitudinal, central section of the tank were measured with an acoustical Doppler velocimeter in a grid net for the different contact zone configurations, giving an insight into the flow structure. The result showed that the flow structure in the contact zone was characterised by a turbulent lower region and a plug-flow higher region. The hydraulic surface loading, a function of the length of the contact zone, seemingly determined the extension of the turbulent region. A higher hydraulic surface loading decreased the turbulent region while the lower loading increased it. A hydraulic surface loading of 65 m/h was suggested for design. It was not possible to determine the turbulent intensity quantitatively due to the measurement method. The height and inclination of the shaft wall did not seem to have a significant influence on the turbulent region. However, an increased height of the contact zone enhanced the higher, plug flow region and a recommended height of 0.81 m or higher for the recommended hydraulic surface loading was suggested when both mixing and plug-flow are desired. The separation zone was characterised by a stratified flow structure, mainly influenced by the cross-flow velocity that is a function of the distance between the shaft wall top and the water surface. A cross-flow velocity of 37m/h or higher resulted in a clearly defined stratification, believed to be crucial for an efficient separation of flocs. Finally, the extension of the lower, denser plug-flow region in the separation zone increased when the shaft wall height increased. 相似文献
27.
The sequence of estimates formed by the LMS algorithm for a standard linear regression estimation problem is considered. It is known since earlier that smoothing these estimates by simple averaging will lead to, asymptotically, the recursive least-squares algorithm. In this paper, it is first shown that smoothing the LMS estimates using a matrix updating will lead to smoothed estimates with optimal tracking properties, also in case the true parameters are slowly changing as a random walk. The choice of smoothing matrix should be tailored to the properties of the random walk. Second, it is shown that the same accuracy can be obtained also for a modified algorithm, SLAMS, which is based on averages and requires much less computations. 相似文献
28.
Lennart Björneborn 《Scientometrics》2006,68(3):395-414
Summary Combining webometric and social network analytic approaches, this study developed a methodology to sample and identify Web
links, pages, and sites that function as small-world connectors affecting short link distances along link paths between different
topical domains in an academic Web space. The data set comprised 7669 subsites harvested from 109 UK universities. A novel
corona-shaped Web graph model revealed reachability structures among the investigated subsites. Shortest link path netsfunctioned
as investigable small-world link structures - 'mini small worlds' - generated by deliberate juxtaposition of topically dissimilar subsites. Indicative findings suggest that personal Web page
authors and computer science subsites may be important small-world connectors across sites and topics in an academic Web space.
Such connectors may counteract balkanization of the Web into insularities of disconnected and unreachable subpopulations. 相似文献
29.
The problem to estimate transfer functions of linear systems is considered. The quality of the resulting estimate depends, among other things, on the input used during the identification experiment. We measure the quality using a quadratic norm in the frequency domain. The problem to determine optimal inputs, i.e. inputs that minimize the chosen norm, subject to constrained input variance, has long been studied. We point out that such procedures may involve a prejudice (that the system is to be found in a certain model set) that may have some surprising effects. We discuss how such a prejudice can be reduced by allowing the possibility that the true system cannot be exactly described in the chosen model set. We also calculate explicit expressions for the resulting “unprejudiced” optimal inputs. These expressions relate the signal-to-noise ratio (as a function of frequency) to the chosen weighting function in the quadratic norm. We also point out the role of the employed noise model for the design. 相似文献
30.
Lennart Åqvist 《Artificial Intelligence and Law》2007,15(4):391-410
The purpose of this paper is to improve on the logical and measure-theoretic foundations for the notion of probability in the law of evidence, which were given in my contributions Åqvist [ (1990) Logical analysis of epistemic modality: an explication of the Bolding–Ekelöf degrees of evidential strength. In: Klami HT (ed) Rätt och Sanning (Law and Truth. A symposium on legal proof-theory in Uppsala May 1989). Iustus Förlag, Uppsala, pp 43–54; (1992) Towards a logical theory of legal evidence: semantic analysis of the Bolding–Ekelöf degrees of evidential strength. In: Martino AA (ed) Expert systems in law. Elsevier Science Publishers BV, Amsterdam, North-Holland, pp 67–86]. The present approach agrees with the one adopted in those contributions in taking its main task to be that of providing a semantic analysis, or explication, of the so called Bolding–Ekelöf degrees of evidential strength (“proof-strength”) as applied to the establishment of matters of fact in law-courts. However, it differs from the one advocated in our earlier work on the subject in explicitly appealing to what is known as “Pro-et-Contra Argumentation”, after the famous Norwegian philosopher Arne Naess. It tries to bring out the logical form of that interesting kind of reasoning, at least in the context of the law of evidence. The formal techniques used here will be seen to be largely inspired by the important work done by Patrick Suppes, notably Suppes [(1957) Introduction to logic. van Nostrand, Princeton and (1972) Finite equal-interval measurement structures. Theoria 38:45–63]. 相似文献