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161.
JA Monn MJ Valli BG Johnson CR Salhoff RA Wright T Howe A Bond D Lodge LA Spangle JW Paschal JB Campbell K Griffey JP Tizzano DD Schoepp 《Canadian Metallurgical Quarterly》1996,39(15):2990-3000
The four isomers of 4-aminopyrrolidine-2,4-dicarboxylate (APDC) were prepared and evaluated for their effects at glutamate receptors in vitro. (2R,4R)-APDC (2a), an aza analog of the nonselective mGluR agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate (1S,3R)-ACPD, 1), was found to possess relatively high affinity for metabotropic glutamate receptors (mGluRs) (ACPD-sensitive [3H]glutamate binding IC50 = 6.49 +/- 1.21 microM) with no effects on radioligand binding to NMDA, AMPA, or kainate receptors up to 100 microM. None of the other APDC isomers showed significant mGluR binding affinity, indicating that this interaction is highly stereospecific. Both 1 and 2a were effective in decreasing forskolin-stimulated cAMP formation in the adult rat cerebral cortex (EC50 = 8.17 +/- 2.21 microM for 1; EC50 = 14.51 +/- 5.54 microM for 2a); however, while 1 was also effective in stimulating basal tritiated inositol monophosphate production in the neonatal rat cerebral cortex (EC50 = 27.7 +/- 5.2 microM), 2a (up to 100 microM) was ineffective in stimulating phosphoinositide hydrolysis in this tissue preparation, further supporting our previous observations that 2a is a highly selective agonist for mGluRs negatively coupled to adenylate cyclase. Microelectrophoretic application of either 1 or 2a to intact rat spinal neurons produced an augmentation of AMPA-induced excitation (95 +/- 10% increase for 1, 52 +/- 6% increase for 2a). Intracerebral injection of 1 (400 nmol) produced characteristic limbic seizures in mice which are not mimicked by 2a (200-1600 nmol, ic). However, the limbic seizures induced by 1 were blocked by systemically administered 2a in a dose-dependent manner (EC50 = 271 mg/kg, ip). It is concluded that (2R,4R)-APDC (2a) is a highly selective, systemically-active agonist of mGluRs negatively coupled to adenylate cyclase and that selective activation of these receptors in vivo can result in anticonvulsant effects. 相似文献
162.
163.
V Kumar PM Carabateas JA Dority WG Earley JP Mallamo C Subramanyam LD Aimone B Ault DL DeHaven Hudkins MS Miller 《Canadian Metallurgical Quarterly》1995,38(10):1826-1830
Replacement of the pyridinium ring of 6,11-ethanobenzo[b]quinolizinium cations with thiazolium (4a and 4b) and N-methylimidazolium (4c and 4d) resulted in equipotent compounds in the [3H]TCP binding assay. The corresponding N-methyl-1,2,4-triazolium analogs were less potent in this assay. The thiazolium derivative 4b, with a Ki = 2.9 nM, is being evaluated as a possible neuroprotective N-methyl-D-aspartic acid (NMDA) antagonist. 相似文献
164.
KL Min JP Steghens R Henry A Doutheau C Collombel 《Canadian Metallurgical Quarterly》1996,238(2):446-452
Fourteen new creatine analogues, all with a guanidine function and either a polar or an apolar group instead of the creatine carboxylic function, were tested as potential inhibitors for human creatine kinase by kinetic analysis of their effects on the reaction rate. Only compounds bearing an apolar aromatic moiety, which was spaced from the guanidine function by at least two bonds, proved to have a significant inhibitory activity and showed a mixed-type inhibition similar to that of creatine. Among these compounds 2,6-dichlorobenzylguanidine (Ki = 5.6 mM and 39.8 mM for muscle-type and brain-type creatine kinases, respectively) and 3-(2,6-dichlorophenyl)propylguanidine (Ki = 15 mM and 4.5 mM) were the more potent inhibitors and showed a significant isoenzyme selectivity between muscle- and brain-type creatine kinases. Our results are in agreement with recent data that suggest the location of a hydrophobic pocket near the guanidine-binding domain of the enzyme. The observed selectivity in isoenzyme inhibition may be useful to study structural differences in catalytic centers. 相似文献
165.
166.
Standard techniques measuring heart rate (HR) variability do not account for its dependence on the rate and depth of respiration or measure the time relationship between changes in lung volume and HR. We used transfer function analysis to determine the magnitude and time relationship of the HR response to a known change in lung volume in controls and diabetics. This technique demonstrated significant differences between controls and diabetics with varying degrees of autonomic dysfunction. Specifically, reduced supine vagal and increased supine sympathetic HR modulation was found with progression of the autonomic neuropathy. In response to postural change the normal diabetics displayed impaired sympathetic HR modulation. Transfer function analysis yields new insight into the sequence of changes that occur with diabetic autonomic neuropathy and provides an accurate, easily comprehensible measurement of respiratory induced HR variability. 相似文献
167.
G Fernandez-Ballester F Gavilanes JP Albar M Criado JA Ferragut JM Gonzalez-Ros 《Canadian Metallurgical Quarterly》1995,68(3):858-865
The conformation of the inactivating peptide of the Shaker B K+ channel (ShB peptide) and that of a noninactivating mutant (ShBL7E peptide) have been studied. Under all experimental conditions explored, the mutant peptide remains in a predominantly nonordered conformation. On the contrary, the inactivating ShB peptide has a great tendency to adopt a highly stable beta structure, particularly when challenged "in vitro" by anionic phospholipid vesicles. Because the putative peptide binding elements at the inner mouth of the channel comprise a ring of anionic residues and a hydrophobic pocket, we hypothesize that the conformational restrictions imposed on the ShB peptide by its interaction with the anionic lipid vesicles could partly imitate those imposed by the above ion channel elements. Thus, we propose that adoption of beta structure by the inactivating peptide may also occur during channel inactivation. Moreover, the difficulties encountered by the noninactivating ShBL7E peptide mutant to adopt beta structure and the observation that trypsin hydrolysis of the ShB peptide prevent both structure formation and channel inactivation lend further support to the hypothesis that adoption of beta structure by the inactivating peptide in a hydrophobic environment is important in determining channel blockade. 相似文献
168.
WN Roberts JP Brodeur J DeWitt SZ Carr CM Wise ME Carr 《Canadian Metallurgical Quarterly》1996,47(11):1081-1087
Electroimmunodiffusion (Laurell rocket) determinations of factor VIII-related antigen in plasma were ordered to determine the cost/benefit ratio for factor VIII-related antigen as a putative test for endothelial damage in suspected vasculitis. Twenty-seven consecutive patients referred for vasculitis or suspected vasculitis were identified and followed up for an average of 9.1 +/- months (range: one to thirty-three months) in a prospective, unblinded study performed in a clinic, associated with a 1054-bed inner-city university hospital. There was no difference in Westergren erythrocyte sedimentation rate (WESR) in patients with final diagnosis of systemic vasculitis (SV) (38 +/- 12 mm/hour) compared to those without vasculitis (NV) (27 +/- 7) as the final diagnosis. The mean plasma concentration of factor VIII-related antigen was significantly elevated in SV (344 +/- 100%) when compared with NV (147 +/- 39%) (P < 0.016). The factor VIII-related antigen test in this study was 2.56 times more likely (crude odds ratio) than the WESR to contribute to a change in diagnosis or therapy (P = 0.016). Positive and negative predictive values (PPV and NPV) for factor VIII-related antigen (abnormal at greater than 220% of the normal value) were both 70%. PPV and NPV for WESR were 56% and 86%, respectively. The factor VIII-related test was less cost-effective than the WESR in the follow-up period unless it was important to define complete remission or differentiate vasculitis flare from infection. The authors conclude that factor VIII-related antigen is a useful test in the initial diagnosis of vasculitis. 相似文献
169.
OP Kreyden U Herzog C Ackermann JP Schuppisser HP Spichtin P Tondelli 《Canadian Metallurgical Quarterly》1996,126(36):1536-1540
Bowen's disease of the anal region is a rare, slow-growing, intraepidermal squamous-cell carcinoma (carcinoma in situ). If surgical excision is incomplete, there is a risk of subsequent development of malignancy and metastasis. Between 1980 and 1995 we treated 11 patients (8 female, 3 male) with anal Bowen's disease. The mean age was 55 (34-75) years. The main reason for excision was: pain (4), itching (3), bleeding (3) and a disturbing lump (3). The intraoperative findings were in all cases a lesion at the anocutaneous line: perianal or intra-anal tumor (6), erosion (2) or ulceration (2) as well as lichenoid lesion (4) or hyperpigmentation (3). The procedure was excision of the lesion in 10 cases. Only in one case was a biopsy taken. 3 patients had to be operated on a second time for reasons of radicality. 5 years after primary diagnosis, one patient developed a recurrent invasive squamous-cell carcinoma and had to undergo perineo-abdominal rectum amputation with postoperative radiotherapy (2 years after operation). Only one patient underwent a biopsy, which produced the diagnosis of invasive squamous-cell carcinoma. He underwent combined chemo-radiotherapy. The symptoms of anal Bowen's disease are unspecific and the clinical findings are uncharacteristic. The recommended therapy is complete surgical excision. With complete excision no recurrences do occur. 相似文献
170.