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排序方式: 共有1010条查询结果,搜索用时 15 毫秒
1.
Francesco Traccis Valeria Serra Claudia Sagheddu Mauro Congiu Pierluigi Saba Gabriele Giua Paola Devoto Roberto Frau Joseph Francois Cheer Miriam Melis 《International journal of molecular sciences》2021,22(4)
Cannabis use among pregnant women is increasing worldwide along with permissive sociocultural attitudes toward it. Prenatal cannabis exposure (PCE), however, is associated with adverse outcome among offspring, ranging from reduced birth weight to child psychopathology. We have previously shown that male rat offspring prenatally exposed to Δ9-tetrahydrocannabinol (THC), a rat model of PCE, exhibit extensive molecular, cellular, and synaptic changes in dopamine neurons of the ventral tegmental area (VTA), resulting in a susceptible mesolimbic dopamine system associated with a psychotic-like endophenotype. This phenotype only reveals itself upon a single exposure to THC in males but not females. Here, we characterized the impact of PCE on female behaviors and mesolimbic dopamine system function by combining in vivo single-unit extracellular recordings in anesthetized animals and ex vivo patch clamp recordings, along with neurochemical and behavioral analyses. We find that PCE female offspring do not show any spontaneous or THC-induced behavioral disease-relevant phenotypes. The THC-induced increase in dopamine levels in nucleus accumbens was reduced in PCE female offspring, even when VTA dopamine activity in vivo and ex vivo did not differ compared to control. These findings indicate that PCE impacts mesolimbic dopamine function and its related behavioral domains in a sex-dependent manner and warrant further investigations to decipher the mechanisms determining this sex-related protective effect from intrauterine THC exposure. 相似文献
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Dr. Blijke S. Kroezen Gabriele Conti Benedetta Girardi Dr. Jonathan Cramer Dr. Xiaohua Jiang Dr. Said Rabbani Jennifer Müller Maja Kokot Enrico Luisoni Prof. Daniel Ricklin Dr. Oliver Schwardt Prof. Beat Ernst 《ChemMedChem》2020,15(18):1706-1719
Siglecs are members of the immunoglobulin gene family containing sialic acid binding N-terminal domains. Among them, Siglec-8 is expressed on various cell types of the immune system such as eosinophils, mast cells and weakly on basophils. Cross-linking of Siglec-8 with monoclonal antibodies triggers apoptosis in eosinophils and inhibits degranulation of mast cells, making Siglec-8 a promising target for the treatment of eosinophil- and mast cell-associated diseases such as asthma. The tetrasaccharide 6’-sulfo-sialyl Lewisx has been identified as a specific Siglec-8 ligand in glycan array screening. Here, we describe an extended study enlightening the pharmacophores of 6’-sulfo-sialyl Lewisx and the successful development of a high-affinity mimetic. Retaining the neuraminic acid core, the introduction of a carbocyclic mimetic of the Gal moiety and a sulfonamide substituent in the 9-position gave a 20-fold improved binding affinity. Finally, the residence time, which usually is the Achilles tendon of carbohydrate/lectin interactions, could be improved. 相似文献
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Alessandro Sannino Dr. Elena Gabriele Martina Bigatti Dr. Sara Mulatto Dr. Jacopo Piazzi Dr. Jörg Scheuermann Prof. Dr. Dario Neri Dr. Etienne J. Donckele Dr. Florent Samain 《Chembiochem : a European journal of chemical biology》2019,20(7):955-962
DNA-encoded chemical libraries are often used for the discovery of ligands against protein targets of interest. These large collections of DNA-barcoded chemical compounds are typically screened by using affinity capture methodologies followed by PCR amplification and DNA sequencing procedures. However, the performance of individual steps in the selection procedures has been scarcely investigated, so far. Herein, the quantitative analysis of selection experiments, by using three ligands with different affinity to carbonic anhydrase IX as model compounds, is described. In the first set of experiments, quantitative PCR (qPCR) procedures are used to evaluate the recovery and selectivity for affinity capture procedures performed on different solid-phase supports, which are commonly used for library screening. In the second step, both qPCR and analysis of DNA sequencing results are used to assess the recovery and selectivity of individual carbonic anhydrase IX ligands in a library, containing 360 000 compounds. Collectively, this study reveals that selection procedures can be efficient for ligands with sub-micromolar dissociation constants to the target protein of interest, but also that selection performance dramatically drops if 104 copies per library member are used as the input. 相似文献
5.
Eva-Maria Herrlinger Mirjam Hau Dr. Desiree Melanie Redhaber Dr. Gabriele Greve Dr. Dominica Willmann Simon Steimle Prof. Dr. Michael Müller Prof. Michael Lübbert Dr. Christoph Cornelius Miething Prof. Roland Schüle Prof. Manfred Jung 《Chembiochem : a European journal of chemical biology》2020,21(16):2329-2347
Lysine-specific demethylase 1 (LSD1) has evolved as a promising therapeutic target for cancer treatment, especially in acute myeloid leukaemia (AML). To approach the challenge of site-specific LSD1 inhibition, we developed an enzyme-prodrug system with the bacterial nitroreductase NfsB (NTR) that was expressed in the virally transfected AML cell line THP1-NTR+. The cellular activity of the NTR was proven with a new luminescent NTR probe. We synthesised a diverse set of nitroaromatic prodrugs that by design do not affect LSD1 and are reduced by the NTR to release an active LSD1 inhibitor. The emerging side products were differentially analysed using negative controls, thereby revealing cytotoxic effects. The 2-nitroimidazolyl prodrug of a potent LSD1 inhibitor emerged as one of the best prodrug candidates with a pronounced selectivity window between wild-type and transfected THP1 cells. Our prodrugs are selectively activated and release the LSD1 inhibitor locally, proving their suitability for future targeting approaches. 相似文献
6.
Antonio Bonati Gabriele Pisano Gianni Royer Carfagni 《Journal of the American Ceramic Society》2020,103(4):2741-2756
Glass plies can be bonded together by polymeric interlayers to form laminated glass. Thanks to the capacity in finding alternative stress paths after partial breakage, it is commonly accepted that the more the layers are, the higher the safety level is. However, a negative aspect is that the tensile strength of glass carries a size effect in terms of surface area, which increases with lamination. Here we evaluate these competing factors by calibrating the partial safety factors to be used in semi-probabilistic (level-I) design, through comparison with probabilistic (level-III) methods in paradigmatic case-studies under wind, snow, and dead weight. Starting from a two-parameter Weibull distribution for glass strength, the “failure modes” approach determines the statistical distribution of strength for a multi-laminate as a function of the number of plies, which interferes with the statistics for actions. As a function of the target probability of failure for the assigned class of consequence, we introduce a new coefficient in the verification formula of level-I, to account for the effects of lamination with dependence upon the number of plies. We find that there is strong gain when passing from a monolith to a two-ply laminate, but the advantage fades by increasing the number of layers. Verification formulas of this type could avoid overconservative design. 相似文献
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With the aim of validating a new standardized Coaxial Double Ring testing procedure, without overpressure and with fixed geometry, an ad hoc theoretical approach has been proposed here to rearrange the laboratory outcomes accounting for the effects of the geometric non-linearities associated with such a testing configuration. By borrowing this idea, once the experimental values of the failure load have been determined, it has been possible to obtain an expression in closed form (fully defined by only two coefficients) of the maximum tensile stress (σmax) in the core of the specimen. Following this, in order to make the laboratory outcomes comparable and homogeneous, the σmax-values have been then re-scaled to a common reference condition (equibiaxial stress on a reference area, σeqbx), by means of the use of a correction coefficient (K) able to determine, under a condition of equal probability of failure, the effective area (Aeff) of the tested specimens. After being corrected to account for the effects of the stress corrosion cracking (static fatigue effect), all re-scaled data have been finally interpreted using a Weibull-type statistical distribution to determine the main fractile values of the glass strength. Doing so, despite some unavoidable approximations, this procedure furnished a highly effective means of determining the bending strength of float glass. Unlike the pure numerical approach proposed in codes and literature, which requires to correct the experimental data via FEM simulation, the rationale behind the proposed approach is in fact to elaborate the experimental data through an analytic treatment of the problem, which would greatly facilitate the interpretation of the data as well as the standardization of the testing procedure. 相似文献
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Synthesis and Biological Evaluation of Papain‐Family Cathepsin L‐Like Cysteine Protease Inhibitors Containing a 1,4‐Benzodiazepine Scaffold as Antiprotozoal Agents 下载免费PDF全文
Dr. Roberta Ettari Dr. Andrea Pinto Dr. Lucia Tamborini Dr. Ilenia C. Angelo Prof. Silvana Grasso Prof. Maria Zappalà Dr. Natale Capodicasa Dr. Laura Yzeiraj Dr. Esther Gruber Dr. Makoah N. Aminake Dr. Gabriele Pradel Prof. Tanja Schirmeister Prof. Carlo De Micheli Prof. Paola Conti 《ChemMedChem》2014,9(8):1817-1825
Novel papain‐family cathepsin L‐like cysteine protease inhibitors endowed with antitrypanosomal and antimalarial activity were developed, through an optimization study of previously developed inhibitors. In the present work, we studied the structure–activity relationships of these derivatives, with the aim to develop new analogues with a simplified and more synthetically accessible structure and with improved antiparasitic activity. The structure of the model compounds was significantly simplified by modifying or even eliminating the side chain appended at the C3 atom of the benzodiazepine scaffold. In addition, a simple methylene spacer of appropriate length was inserted between the benzodiazepine ring and the 3‐bromoisoxazoline moiety. Several rhodesain and falcipain‐2 inhibitors displaying single‐digit micromolar or sub‐micromolar antiparasitic activity against one or both parasites were identified, with activities that were one order of magnitude more potent than the model compounds. 相似文献