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排序方式: 共有307条查询结果,搜索用时 125 毫秒
301.
302.
Vicker N Lawrence HR Allan GM Bubert C Smith A Tutill HJ Purohit A Day JM Mahon MF Reed MJ Potter BV 《ChemMedChem》2006,1(4):464-481
17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1), an oxidoreductase which has a preferential reductive activity using NADPH as cofactor, converts estrone to estradiol and is expressed in many steroidogenic tissues including breast and in malignant breast cells. As estradiol stimulates the growth and development of hormone-dependent breast cancer, inhibition of the final step of its synthesis is an attractive target for the treatment of this disease. The parallel synthesis of novel focused libraries of 16-substituted estrone derivatives and modified E-ring pyrazole steroids as new potent 17beta-HSD1 inhibitors is described. Substituted 3-O-sulfamoylated estrone derivatives were used as templates and were immobilised on 2-chlorotrityl chloride resin to give resin-bound scaffolds with a multi-detachable linker. Novel focused libraries of 16-substituted estrone derivatives and new modified E-ring steroids were assembled from these immobilised templates using solid-phase organic synthesis and solution-phase methodologies. Among the derivatives synthesised, the most potent 17beta-HSD1 inhibitors were 25 and 26 with IC50 values in T-47D human breast cancer cells of 27 and 165 nm, respectively. Parallel synthesis resulting in a library of C5'-linked amides from the pyrazole E-ring led to the identification of 62 with an IC50 value of 700 nM. These potent inhibitors of 17beta-HSD1 have a 2-ethyl substituent which will decrease their estrogenic potential. Several novel 17beta-HSD1 inhibitors emerged from these libraries and these provide direction for further template exploration in this area. A new efficient diastereoselective synthesis of 25 has also been developed to facilitate supply for in vivo evaluation, and an X-ray crystal structure of this inhibitor is presented. 相似文献
303.
The aim of this work was to develop a stable injectable formulation of the antimalarial drug halofantrine (Hf) based on nanocapsules (NC) prepared from biodegradable polymers with Miglyol 810N as the oily core. Poly(D,L-lactide) PLA and its copolymers with poly(ethyleneglycol) (PLA-PEG) were used together with the surfactants poloxamer 188 and lecithin to yield NC with different surface properties. Highly efficient loading of the free base form of Hf was obtained; zeta potential measurements indicated that a part of the associated Hf was at the NC surface, interacting with the lecithin. NC were 150-250 nm in diameter and more stable on storage than nanoemulsions formed from oil and lecithin without polymer. The most stable NC, showing minimal size changes and flocculation, were those with a high density of 20-kDa PEG chains covalently grafted at the surface. Hf release from NC occurred mainly by partition with the external medium. In PBS, even when Tween 80 was added, release was limited to 20% of the total content, whatever the formulation. Addition of serum to the medium allowed complete and rapid release from PLA NC stabilized with adsorbed poloxamer 188, because of the high affinity of Hf for lipoproteins. However, the presence of covalently grafted PEG chains at the surface limited release by providing a hydrophilic steric barrier at the particle surface. A dense coverage with long PEG chains provided the best reduction of release. Such systems could constitute a long-circulating intravenous formulation of Hf for treating severe malaria. 相似文献
304.
Keith A. Smith Iain P. McTaggart Karen E. Dobbie Franz Conen 《Nutrient Cycling in Agroecosystems》1998,52(2-3):123-130
Potato fields and cut (ungrazed) grassland in SE Scotland gave greater annual N2O emissions per ha (1.0–3.2 kg N2O–N ha-1) than spring barley or winter wheat fields (0.3–0.8 kg N2O–N ha-1), but in terms of emission per unit of N applied the order was potatoes > barley > grass > wheat. On the arable land, especially the potato fields, a large part of the emissions occurred after harvest.When the grassland data were combined with those for 2 years' earlier work at the same site, the mean emission over 3 years, for fertilization with ammonium nitrate, was 2.24 kg N2O–N ha-1 (0.62% of the N applied). Also, a very strong relationship between N2O emission and soil nitrate content was found for the grassland, provided the water-filled pore space was > 70%. Significant relationships were also found between the emissions from potato fields and the soil mineral N content, with the added feature that the emission per unit of soil mineral N was an order of magnitude larger after harvest than before, possibly due to the effect of labile organic residues on denitrification.Generally the emissions measured were lower, as a function of the N applied, than those used as the basis for the current value adopted by IPCC, possibly because spring/early summer temperatures in SE Scotland are lower than those where the other data were obtained. The role of other factors contributing to emissions, e.g. winter freeze–thaw events and green manure inputs, are discussed, together with the possible implications of future increases in nitrogen fertilizer use in the tropics. 相似文献
305.
Gillian Ysart Patrick Miller Helen Crews Paul Robb Malcolm Baxter Christian De L'Argy Simon Lofthouse Christine Sargent Nigel Harrison 《Food Additives & Contaminants》1999,16(9):391-403
Dietary exposures of consumers to 30 elements (aluminium, antimony, arsenic, barium, bismuth, boron, cadmium, calcium, chromium, cobalt, copper, germanium, gold, iridium, iron, lead, lithium, manganese, mercury, molybdenum, nickel, palladium, platinum, rhodium, ruthenium, selenium, strontium, thallium, tin and zinc) estimated from the UK 1994 Total Diet Study are reported, and compared with those from previous UK Total Diet Studies and those from other countries. Dietary exposure estimates were generally low and, where comparisons are possible, similar to those from other countries and below the relevant Provisional Tolerable Weekly Intakes and Provisional Maximum Tolerable Daily Intakes. For most of those elements included in previous UK Total Diet Studies, dietary exposures have declined. 相似文献
306.
Fawcett Gillian; Heise Lori L.; Isita-Espejel Leticia; Pick Susan 《Canadian Metallurgical Quarterly》1999,54(1):41
This article describes the process of designing a multifaceted, community-based intervention to change community responses to wife abuse in Iztacalco, a low-income community on the outskirts of Mexico City. The goal of the intervention is to encourage women to recognize and disclose abuse and to encourage more constructive, less victim-blaming attitudes among family members, friends, and the community at large. The intervention is based on the belief that the response that a woman first gets upon disclosing her situation will be critical in setting the course of her future actions. The intervention includes small-scale media (e.g., buttons, posters, events) and a 12-session workshop to train women as community change agents. The design is based on insights derived from formative research and from the transtheoretical model of behavior change as elaborated by J. O. Prochaska and C. C. DiClemente (1982) and adapted to the special case of domestic violence by J. Brown (1997). The article also illustrates the utility of adapting popular education techniques to the research setting in order facilitate more honest disclosure of prevailing norms and attitudes about abuse. (PsycINFO Database Record (c) 2010 APA, all rights reserved) 相似文献
307.
Gabriela Daniels Ashiana Fraser Gillian E. Westgate 《International journal of cosmetic science》2023,45(1):50-61
This review critically appraises the reported differences in human hair fibre within three related domains of research: hair classification approaches, fibre characteristics and properties. The most common hair classification approach is based on geo-racial origin, defining three main groups: African, Asian and Caucasian hair. This classification does not account sufficiently for the worldwide hair diversity and intergroups variability in curl, shape, size and colour. A global classification into eight curl types has been proposed but may be too complex for reproducibility. Beyond that, hair cross-sectional shape and area have been found to have an inverse relation to curl: straighter fibres are circular with larger cross-sectional area, whilst the curlier fibres are elliptical with smaller cross-sectional area. These geometrical differences have been associated with bilateral vs homogenous distribution of cortical cell in curly vs straight hair respectively. However, there is no sufficient data demonstrating significant differences in hair amino composition, but proteomic studies are reporting associations of some proteins with curly hair. Eumelanin’s relative abundance has been reported in all hair colours except for red hair which has a high pheomelanin content. Higher tensile and fatigue strength of straight hair are reported, however, curly hair fragility is attributed to knotting, and crack and flow formations rather than the structural variations. African hair has been found to have the highest level of lipids, whilst the water sorption of Caucasian hair is the highest, and that of Asian hair the lowest. Not all comparative studies clearly report their hair sampling approaches. Therefore, to strengthen the robustness of comparative studies and to facilitate cross-study data comparisons, it is recommended that the following hair defining characteristics are reported in studies: hair cross sectional diameter/area, curl type, hair assembly colour, as well as where possible donor data (age/gender) and sample pooling approach. 相似文献