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81.
Synthesis and Biological Evaluation of Papain‐Family Cathepsin L‐Like Cysteine Protease Inhibitors Containing a 1,4‐Benzodiazepine Scaffold as Antiprotozoal Agents
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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
82.
Since 2006 a European map of indoor radon (Rn) concentration is in the making. So far 20 countries have contributed with national data, allowing a fair coverage of parts of Europe. This paper presents the current (September 2010) state of the map, discusses its rationale, presents some statistical findings and addresses a few problems which arose during the work. It also briefly presents the European Atlas of Natural Radiation project, of which the Rn map will be part, and further, planned maps of environmental natural radioactivity. 相似文献
83.
Jonker A Gruber MY Wang Y Coulman B Azarfar A McKinnon JJ Christensen DA Yu P 《Journal of dairy science》2011,94(3):1430-1444
Dairy cattle eating fresh or ensiled alfalfa as the main portion of their diet often have low protein efficiency because of the rapid initial rate of ruminal protein degradation of fresh and ensiled alfalfa. Ruminal protein degradation of alfalfa might be reduced by introducing a gene that stimulates the accumulation of mono- or polymeric anthocyanidins in alfalfa. The objectives of this study were to fractionate protein and carbohydrates by in situ and chemical approaches, to evaluate in situ ruminal degradation characteristics and synchronization ratios, to determine protein availability to dairy cattle using the 2007 digestible intestinal protein/rumen-degraded protein balance (DVE/OEB) protein system, and to determine net energy for lactation using the Dutch net energy for lactation (VEM) system for 3 newly developed transgenic winter hardy anthocyanidin-accumulating T1Lc-alfalfa populations. These T1Lc-alfalfa populations, called T1BeavLc1, T1RambLc3, and T1RangLc4, had an average anthocyanidin accumulation of 163.4 μg/g of DM, whereas AC Grazeland (selected for a low initial rate of degradation) did not accumulate anthocyanidin. The basic chemical composition of the original samples, soluble and potentially degradable fractions, and degradation characteristics of crude protein and carbohydrates were similar in T1Lc-alfalfa and AC Grazeland. The undegradable in situ crude protein and neutral detergent fiber fraction had 1.3% lower CP and 4.8% lower CHO, respectively, in T1Lc-alfalfa compared with the amounts in AC Grazeland. The T1Lc-alfalfa had a 0.34 MJ/kg of DM higher calculated net energy for lactation and 1.9% of CP higher buffer soluble protein compared with that in AC Grazeland. By the protein evaluation model, it was predicted that T1Lc-alfalfa tended to have 11.9, 6.9, and 8.4 g/kg of DM higher rumen degradable protein, OEB, and intestinal available protein, respectively, compared with the amounts in AC Grazeland. The hourly OEB included an initial and substantial peak (oversupply) of protein relative to energy, which was highest in T1RangLc4 and lowest in T1RambLc3. The hourly OEB between 4 and 24 h was similar and more balanced for all 4 alfalfa populations. In conclusion, T1Lc-alfalfa accumulated anthocyanidin, tended to have higher predicted intestinal protein availability, and had higher predicted net energy of lactation availability for dairy cattle than did AC Grazeland. 相似文献
84.
D Grandér R Hultcrantz O Weiland B Xu O Sangfelt AC Bj?rklund R Befrits M Bj?rkholm A Gruber N Kinnman O Reichard A Widell S Einhorn 《Canadian Metallurgical Quarterly》1996,31(6):604-611
BACKGROUND: The mechanism behind the antiviral action of interferon (IFN) therapy in chronic hepatitis C virus (HCV) infection is not well understood, and, furthermore, few factors have been shown to be good predictors of a favourable response to IFN treatment in chronic HCV infection. METHODS: Freshly explanted liver cells and peripheral blood mononuclear cells (PBMC) from 80 patients with chronic HCV infection were used to study the capacity of IFN to induce the enzyme 2',5'-oligoadenylate synthetase (2'5'-AS) in vitro. The HCV genotype was determined in 53 patients. The induction of 2'5'-AS was correlated to the results of IFN-alpha treatment in 36 patients. RESULTS: Normalization of transaminases during IFN treatment was significantly associated with 2'5'-AS levels in liver cells cultured in the absence of IFN. A similar tendency, although not statistically significant, was found for IFN-induced levels of 2'5'-AS in liver cells. No such associations were found when PBMC were analysed. Six patients showed a sustained biochemical response. These six did not deviate significantly from the remaining patients with regard to base-line or IFN-induced levels of 2'5'-AS in liver cells or PBMC. Eradication of HCV RNA during IFN treatment did not correlate with 2'5'-AS levels in liver cells. Comparison of HCV genotype and clinical response showed that patients with genotype 3a had the most favourable outcome. No association was found between liver histology and treatment outcome. CONCLUSION: These data imply that direct effects of IFN on liver cells are of importance for the response to IFN treatment. 相似文献
85.
As with women in general, the vicissitudes of the female physician who suffers from a substance use disorder have been understudied, and such persons remain underrepresented in treatment. The purpose of the present study is to describe the similarities and differences between female and male physicians presenting for assessment; 108 physicians in total were included in the study, 10 of whom were female. Demographically, we found that the female physicians were more likely to be single and younger than their male counterparts. On clinical indices, females showed less impairment on legal and medical functioning, and better capability in sustaining abstinence and eliminating environmental cues to relapse. Of the women with substance use disorders, higher rates of comorbidity were found than with males. Although there were no significant differences in overall severity, males were more likely to be recommended to more intensive levels of care for either substance use or psychiatric disorders. The female physicians were recommended to a level of care of a lower intensity, but more often to a treatment with a dual-diagnosis focus. These findings are discussed in terms of the vulnerabilities of the female physician, barriers to treatment, tailoring treatment to female needs, and opportunities for prevention and further research. 相似文献
86.
R Gandhi RC Elble AD Gruber KD Schreur HL Ji CM Fuller BU Pauli 《Canadian Metallurgical Quarterly》1998,273(48):32096-32101
A protein (mCLCA1) has been cloned from a mouse lung cDNA library that bears strong sequence homology with the recently described bovine tracheal, Ca2+-sensitive chloride channel protein (bCLCA1), bovine lung endothelial cell adhesion molecule-1 (Lu-ECAM-1), and the human intestinal Ca2+-sensitive chloride channel protein (hCLCA1). In vitro, its 3.1-kilobase message translates into a 100-kDa protein that can be glycosylated to an approximately 125-kDa product. SDS-polyacrylamide gel electrophoresis from lysates of mCLCA1 cDNA-transfected transformed human embryonic kidney cells (HEK293) reveals proteins of 130, 125, and 90 kDa as well as a protein triplet in the 32-38 kDa size range. Western analyses with antisera raised against Lu-ECAM-1 peptides show that the N-terminal region of the predicted open reading frame is present only in the larger size proteins (i.e. 130, 125, and 90 kDa), whereas the C-terminal region of the open reading frame is observed in the 32-38 kDa size proteins, suggesting a posttranslational, proteolytic processing of a precursor protein (125/130 kDa) into 90 kDa and 32-38 kDa components similar to that reported for Lu-ECAM-1. Hydrophobicity analyses predict four transmembrane domains for the 90-kDa protein. The mCLCA1 mRNA is readily detected by Northern analysis and by in situ hybridization in the respiratory epithelia of trachea and bronchi. Transient expression of mCLCA1 in HEK293 cells was associated with an increase in whole cell Cl- current that could be activated by Ca2+ and ionomycin and inhibited by 4, 4'-diisothiocyanatostilbene-2,2'-disulfonic acid, dithiothreitol, and niflumic acid. The discovery of mCLCA1 opens the door for further investigating the possible contribution of a Ca2+-sensitive chloride conductance to the pathogenesis of cystic fibrosis. 相似文献
87.
H Mahalingam J Vaughn J Novotny JR Gruber RM Niles 《Canadian Metallurgical Quarterly》1996,168(3):549-558
Serotonergic neuronal networks are important for food intake and body weight regulation. Dexfenfluramine (dF), a serotonin releaser and reuptake inhibitor, was used to investigate changes in food intake, body weight development, energy expenditure, respiratory quotient, and substrate oxidation rates for 12 days. Rats, which had been made obese by early postnatal overfeeding, received an energy-controlled mash diet and water ad lib and were intraperitoneally injected daily with either saline, 5 or 10 mg dF/kg. Compared to controls, food intake, body weight development, and energy expenditure were decreased in a dose-dependent manner, especially during the first 6 days. Lipid oxidation was increased while oxidation of carbohydrates was decreased. Pair-feeding experiments over 2 days revealed that this was not solely a result of diminished food intake but also an additional metabolic effect of dF, different from its anorectic effect. At the end of these experiments, plasma glucose and liver glycogen were unchanged after dF, but plasma free fatty acids were significantly decreased. Insulin-sensitivity was probably improved, indicated by decreased insulin levels and increases in muscle glycogen contents and activities of muscle pyruvate kinase. Liver-glutamine and contents of valine, leucine, and isoleucine in the muscle were significantly decreased after dF-treatment, the latter indicating a diminished proteolysis. The plasma tryptophan/large neutral amino acids ratio of the dF-rats was unchanged but that of the paired-fed rats was changed, despite similar changes in food intake. It is concluded that both increased oxidation of endogenous fat and reduced food intake could mediate the body weight reducing effect of dF. 相似文献
88.
EDnline PhillippeRabier StephaneSerrier 《电子设计应用》2003,(9):66-67
异步数字用户线路(ADSL)调制解调器由于同普通电话线相连,容易遭受电击。因此,必须施加恰当保护,以抵抗破坏性过压和压流的冲击。通晓保护标准、指导原则和器件,可以提高设计人员保护ADSL调制解调器的电话线及数据线免遭过压冲击的能力。如表1所示,标准的选择取决于设备类型、在网络中的位置和网络的地理区域。对于并联元器件,特别是具有急剧短路特性的器件,可以提供必要的雷电冲击保护功能。急剧短路器件的优点是可以高效地短接电话双绞线,消除过压,而且热量极小。在正常电压下,急剧短路器件保持开路状态。器件的电流处理能力取决于器… 相似文献
89.
Histochemical characterisation of unextractable seed coat pigments and quantification of extractable lignin in the Brassicaceae 总被引:1,自引:0,他引:1
MA Susan Marles Margaret Y Gruber 《Journal of the science of food and agriculture》2004,84(3):251-262
The differences determined by in situ histochemical staining and thioglycolic lignin analyses provided a new view of seed coat composition in a range of yellow‐ and brown‐seeded germplasm of the Brassicaceae. Unextractable seed coat pigments were composed of proanthocyanidin (condensed tannin) polymers. Anthocyanins were absent in all seed coat tissues. Proanthocyanidin was deposited over the entire seed coat in dark‐seeded germplasm and in patches in some yellow‐seeded germplasm. The seed coat and hilum of Crambe abyssinica cv Prophet and some yellow‐seeded accessions contained an unidentified, unreactive brown pigment. Several new pigmentation patterns, occurring as spots and patches and surrounding the hilum, became apparent from this analysis. Thioglycolic lignin was significantly lower in yellow‐seeded samples compared with the dark‐seeded accessions, and the majority of the lignin occurred in the seed coat. These discoveries provide new and useful data for plant breeders and indicate the need to use more detailed analytical methods in breeding programmes that have the goal of improving seed meal quality by reducing fibre and phenolics. Copyright © 2004 Society of Chemical Industry 相似文献
90.